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Skok K, Stift J, Schirmacher P, Kashofer K, Stauber R, Ranković B, Lackner K. Molecular Landscape and Treatment Paradigms of Hepatocellular and Cholangiocarcinoma: A Multinational Review. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2025. [PMID: 40164125 DOI: 10.1055/a-2548-0108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) represent the most prevalent primary liver cancers and pose significant challenges in oncology. While their etiology and incidence vary globally, the molecular landscape of these tumors is increasingly understood, offering new opportunities for precision medicine. In this joint multinational review, we present a comprehensive analysis of the key molecular pathways involved in the pathogenesis of HCC and CCA, highlighting actionable targets for emerging therapies. Recent advances in molecular diagnostics have significantly influenced treatment paradigms for both cancers. In HCC, while genetic alterations have not yet led to established diagnostic or therapeutic applications, targeting vascular endothelial growth factor (VEGF), immune checkpoints, and tyrosine kinase pathways has demonstrated considerable therapeutic potential. In CCA, genetic profiling has uncovered actionable alterations, such as FGFR2 fusions and IDH1 mutations, driving the development of targeted therapies. The growing complexity of precision oncology underscores the need for standardized molecular testing and streamlined diagnostic workflows to ensure timely and effective treatment. This review also emphasizes the importance of collaborative efforts between clinicians, pathologists, and oncologists to optimize outcomes. By synthesizing the latest molecular insights and treatment trends, this review provides a valuable resource to guide the personalized management of HCC and CCA.
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Affiliation(s)
- Kristijan Skok
- Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria
- Insitute of Biomedical Sciences, Faculty of Medicine University of Maribor in Slovenia, Maribor, Slovenia
| | - Judith Stift
- Institute of Pathology, Versorgungspathologie of the University Clinic of Innsbruck, INNPATH GmbH, Innsbruck, Austria
- ADK Diagnostics, Center for Liver and Pancreatic Pathology, Vienna, Austria
| | - Peter Schirmacher
- Heidelberg University Hospital Institute of Pathology, Heidelberg, Germany
| | - Karl Kashofer
- Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Rudolf Stauber
- Internal Medicine, Medical University of Graz, Graz, Austria
| | - Branislava Ranković
- Institute of Pathology, University of Ljubljana Faculty of Medicine, Ljubljana, Slovenia
| | - Karoline Lackner
- Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria
- ADK Diagnostics, Center for Liver and Pancreatic Pathology, Vienna, Austria
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2
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Outla Z, Oyman-Eyrilmez G, Korelova K, Prechova M, Frick L, Sarnova L, Bisht P, Novotna P, Kosla J, Bortel P, Borutzki Y, Bileck A, Gerner C, Rahbari M, Rahbari N, Birgin E, Kvasnicova B, Galisova A, Sulkova K, Bauer A, Jobe N, Tolde O, Sticova E, Rösel D, O'Connor T, Otahal M, Jirak D, Heikenwälder M, Wiche G, Meier-Menches SM, Gregor M. Plectin-mediated cytoskeletal crosstalk as a target for inhibition of hepatocellular carcinoma growth and metastasis. eLife 2025; 13:RP102205. [PMID: 40052672 DOI: 10.7554/elife.102205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/12/2025] Open
Abstract
The most common primary malignancy of the liver, hepatocellular carcinoma (HCC), is a heterogeneous tumor entity with high metastatic potential and complex pathophysiology. Increasing evidence suggests that tissue mechanics plays a critical role in tumor onset and progression. Here, we show that plectin, a major cytoskeletal crosslinker protein, plays a crucial role in mechanical homeostasis and mechanosensitive oncogenic signaling that drives hepatocarcinogenesis. Our expression analyses revealed elevated plectin levels in liver tumors, which correlated with poor prognosis for HCC patients. Using autochthonous and orthotopic mouse models we demonstrated that genetic and pharmacological inactivation of plectin potently suppressed the initiation and growth of HCC. Moreover, plectin targeting potently inhibited the invasion potential of human HCC cells and reduced their metastatic outgrowth in the lung. Proteomic and phosphoproteomic profiling linked plectin-dependent disruption of cytoskeletal networks to attenuation of oncogenic FAK, MAPK/Erk, and PI3K/Akt signatures. Importantly, by combining cell line-based and murine HCC models, we show that plectin inhibitor plecstatin-1 (PST) is well-tolerated and potently inhibits HCC progression. In conclusion, our study demonstrates that plectin-controlled cytoarchitecture is a key determinant of HCC development and suggests that pharmacologically induced disruption of mechanical homeostasis may represent a new therapeutic strategy for HCC treatment.
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Affiliation(s)
- Zuzana Outla
- Laboratory of Integrative Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Gizem Oyman-Eyrilmez
- Laboratory of Integrative Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Katerina Korelova
- Laboratory of Integrative Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Magdalena Prechova
- Laboratory of Integrative Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Lukas Frick
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Lenka Sarnova
- Laboratory of Integrative Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Piyush Bisht
- Laboratory of Integrative Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Petra Novotna
- Laboratory of Integrative Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Jan Kosla
- Laboratory of Integrative Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
- Division of Chronic Inflammation and Cancer, German Cancer Research Center, Im Neuenheimer Feld, Heidelberg, Germany
| | - Patricia Bortel
- Department of Analytical Chemistry, University of Vienna, Vienna, Austria
| | - Yasmin Borutzki
- Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria
| | - Andrea Bileck
- Department of Analytical Chemistry, University of Vienna, Vienna, Austria
- Joint Metabolome Facility, Medical University of Vienna and University of Vienna, Heidelberg, Germany
| | - Christopher Gerner
- Department of Analytical Chemistry, University of Vienna, Vienna, Austria
- Joint Metabolome Facility, Medical University of Vienna and University of Vienna, Heidelberg, Germany
| | - Mohammad Rahbari
- Division of Chronic Inflammation and Cancer, German Cancer Research Center, Im Neuenheimer Feld, Heidelberg, Germany
- Department of Surgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Nuh Rahbari
- Department of General and Visceral Surgery, Ulm University Hospital, Ulm, Germany
| | - Emrullah Birgin
- Department of General and Visceral Surgery, Ulm University Hospital, Ulm, Germany
| | - Bibiana Kvasnicova
- Department of Natural Sciences, Faculty of Biomedical Engineering, Czech Technical University in Prague, Prague, Czech Republic
| | - Andrea Galisova
- Department of Radiodiagnostic and Interventional Radiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Katerina Sulkova
- Department of Radiodiagnostic and Interventional Radiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Andreas Bauer
- Department of Physics, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Njainday Jobe
- Department of Cell Biology, Faculty of Science, Charles University, BIOCEV, Prumyslova, Vestec, Czech Republic
| | - Ondrej Tolde
- Department of Cell Biology, Faculty of Science, Charles University, BIOCEV, Prumyslova, Vestec, Czech Republic
| | - Eva Sticova
- Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- Department of Pathology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Daniel Rösel
- Department of Cell Biology, Faculty of Science, Charles University, BIOCEV, Prumyslova, Vestec, Czech Republic
| | - Tracy O'Connor
- Department of Biology, North Park University, Chicago, United States
| | - Martin Otahal
- Department of Natural Sciences, Faculty of Biomedical Engineering, Czech Technical University in Prague, Prague, Czech Republic
| | - Daniel Jirak
- Department of Radiodiagnostic and Interventional Radiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Mathias Heikenwälder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center, Im Neuenheimer Feld, Heidelberg, Germany
| | - Gerhard Wiche
- Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria
| | - Samuel M Meier-Menches
- Department of Analytical Chemistry, University of Vienna, Vienna, Austria
- Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria
- Joint Metabolome Facility, Medical University of Vienna and University of Vienna, Heidelberg, Germany
| | - Martin Gregor
- Laboratory of Integrative Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
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3
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Shiode Y, Kodama T, Sato Y, Takahashi R, Matsumae T, Shirai K, Doi A, Tahata Y, Hikita H, Tatsumi T, Fukai M, Taketomi A, Ruchirawat M, Wang XW, Takehara T. Folate receptor 1 is a stemness trait-associated diagnostic and prognostic marker for hepatocellular carcinoma. Biomark Res 2025; 13:37. [PMID: 40038575 DOI: 10.1186/s40364-025-00752-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 02/25/2025] [Indexed: 03/06/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) can be classified into several subtypes based on molecular traits, aiding in prognostic stratification. The subtype with a poor prognosis is often associated with stem/progenitor features. This study focused on identifying circulating biomarkers for aggressive HCC. METHODS We searched for secretory proteins whose expression was positively associated with the stem/progenitor markers KRT19, EPCAM, and PROM1 in 2 independent HCC cohorts. Serum folate receptor 1 (FOLR1) levels were measured in 238 chronic liver disease and 247 HCC patients, evaluating their diagnostic and prognostic capabilities. RESULTS FOLR1 was identified as a secretory protein that was positively correlated with all 3 stem/progenitor markers and a poor prognosis in both the discovery and validation cohorts. Higher FOLR1 expression was detected in tumor than nontumor tissues and was associated with aggressive subtypes, and activation of p53, DNA repair, Myc, E2F, and PI3K/AKT/mTOR pathways. Serum FOLR1 levels correlated with tumoral FOLR1 expression in HCC patients and were significantly elevated compared with those in patients with chronic hepatitis or nonliver disease. Serum FOLR1 levels demonstrated diagnostic performance for HCC comparable to that of alpha-fetoprotein (AFP), and their combination increased the diagnostic accuracy. Elevated serum FOLR1 levels were associated with poor prognosis in HCC patients, regardless of treatment, especially in patients with early-stage disease. The multivariate analysis revealed that the serum FOLR1 level and the Gender, Age, AFP-L3, AFP, and Des-gamma-carboxy prothrombin (GALAD) score were independent predictors of a poor prognosis with their combination further stratifying prognosis. CONCLUSIONS FOLR1 is a stemness-associated biomarker for HCC, with serum levels serving as a diagnostic marker for HCC and a prognostic indicator for early-stage disease.
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Affiliation(s)
- Yuto Shiode
- Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Yu Sato
- Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Ryo Takahashi
- Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Takayuki Matsumae
- Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Kumiko Shirai
- Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Akira Doi
- Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Yuki Tahata
- Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Moto Fukai
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Mathuros Ruchirawat
- Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute, Bangkok, 10210, Thailand
- Center of Excellence On Environmental Health and Toxicology (EHT), OPS, MHESI, Bangkok, Thailand
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan.
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Müller M, May S, Hall H, Kendall TJ, McGarry L, Blukacz L, Nuciforo S, Georgakopoulou A, Jamieson T, Phinichkusolchit N, Dhayade S, Suzuki T, Huguet-Pradell J, Powley IR, Officer-Jones L, Pennie RL, Esteban-Fabró R, Gris-Oliver A, Pinyol R, Skalka GL, Leslie J, Hoare M, Sprangers J, Malviya G, Mackintosh A, Johnson E, McCain M, Halpin J, Kiourtis C, Nixon C, Clark G, Clark W, Shaw R, Hedley A, Drake TM, Tan EH, Neilson M, Murphy DJ, Lewis DY, Reeves HL, Le Quesne J, Mann DA, Carlin LM, Blyth K, Llovet JM, Heim MH, Sansom OJ, Miller CJ, Bird TG. Human-correlated genetic models identify precision therapy for liver cancer. Nature 2025; 639:754-764. [PMID: 39972137 PMCID: PMC11922762 DOI: 10.1038/s41586-025-08585-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 01/02/2025] [Indexed: 02/21/2025]
Abstract
Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause of cancer-related mortality worldwide1,2. HCC occurs typically from a background of chronic liver disease, caused by a spectrum of predisposing conditions. Tumour development is driven by the expansion of clones that accumulate progressive driver mutations3, with hepatocytes the most likely cell of origin2. However, the landscape of driver mutations in HCC is broadly independent of the underlying aetiologies4. Despite an increasing range of systemic treatment options for advanced HCC, outcomes remain heterogeneous and typically poor. Emerging data suggest that drug efficacies depend on disease aetiology and genetic alterations5,6. Exploring subtypes in preclinical models with human relevance will therefore be essential to advance precision medicine in HCC7. Here we generated a suite of genetically driven immunocompetent in vivo and matched in vitro HCC models. Our models represent multiple features of human HCC, including clonal origin, histopathological appearance and metastasis. We integrated transcriptomic data from the mouse models with human HCC data and identified four common human-mouse subtype clusters. The subtype clusters had distinct transcriptomic characteristics that aligned with the human histopathology. In a proof-of-principle analysis, we verified response to standard-of-care treatment and used a linked in vitro-in vivo pipeline to identify a promising therapeutic candidate, cladribine, that has not previously been linked to HCC treatment. Cladribine acts in a highly effective subtype-specific manner in combination with standard-of-care therapy.
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Affiliation(s)
| | - Stephanie May
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Holly Hall
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Timothy J Kendall
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | - Lynn McGarry
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Lauriane Blukacz
- Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland
| | - Sandro Nuciforo
- Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland
| | - Anastasia Georgakopoulou
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | | | - Narisa Phinichkusolchit
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | | | | | - Júlia Huguet-Pradell
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - Ian R Powley
- Cancer Research UK Scotland Institute, Glasgow, UK
| | | | | | - Roger Esteban-Fabró
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - Albert Gris-Oliver
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - Roser Pinyol
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | | | - Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- The Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Matthew Hoare
- Early Cancer Institute, University of Cambridge, Cambridge, UK
- Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | | | | | | | - Emma Johnson
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Misti McCain
- The Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - John Halpin
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Christos Kiourtis
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Colin Nixon
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Graeme Clark
- Cancer Research UK Scotland Institute, Glasgow, UK
| | | | - Robin Shaw
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Ann Hedley
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Thomas M Drake
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh, UK
| | - Ee Hong Tan
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Matt Neilson
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Daniel J Murphy
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - David Y Lewis
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Helen L Reeves
- The Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Liver Group, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - John Le Quesne
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Department of Histopathology, Queen Elizabeth University Hospital, Glasgow, UK
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- The Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
- Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey
| | - Leo M Carlin
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Karen Blyth
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Josep M Llovet
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
| | - Markus H Heim
- Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland
- University Digestive Health Care Center Basel-Clarunis, Basel, Switzerland
| | - Owen J Sansom
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Scotland Centre, Edinburgh, UK
- Cancer Research UK Scotland Centre, Glasgow, UK
| | - Crispin J Miller
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Thomas G Bird
- Cancer Research UK Scotland Institute, Glasgow, UK.
- School of Cancer Sciences, University of Glasgow, Glasgow, UK.
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
- Cancer Research UK Scotland Centre, Edinburgh, UK.
- Cancer Research UK Scotland Centre, Glasgow, UK.
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5
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Myojin Y, Babaei S, Trehan R, Hoffman C, Kedei N, Ruf B, Benmebarek MR, Bauer KC, Huang P, Ma C, Monge C, Xie C, Hrones D, Duffy AG, Armstrong P, Kocheise L, Desmond F, Buchalter J, Galligan M, Cantwell C, Ryan R, McCann J, Bourke M, Mac Nicholas R, McDermott R, Awosika J, Cam M, Krebs R, Budhu A, Revsine M, Figg WD, Kleiner DE, Redd B, Wood BJ, Wang XW, Korangy F, Claassen M, Greten TF. Multiomics analysis of immune correlatives in hepatocellular carcinoma patients treated with tremelimumab plus durvalumab. Gut 2025:gutjnl-2024-334026. [PMID: 39965889 DOI: 10.1136/gutjnl-2024-334026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 02/06/2025] [Indexed: 02/20/2025]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. The combination of tremelimumab and durvalumab is now a standard treatment option for advanced HCC. OBJECTIVE To study immune responses in HCC patients treated with tremelimumab and durvalumab. DESIGN We treated 28 HCC patients with durvalumab, tremelimumab and locoregional therapies. We performed a high-dimensional multiomics analysis including whole exome sequencing, single-cell RNA seq, CO-Detection by indEXing, flow cytometry and multiplex cytokine/chemokine analysis of patients' blood and tumour samples and integrated this data to elucidate immune correlatives and response mechanisms. Mice with syngeneic HCC were treated with anti-PD-L1 plus anti-CTLA4 for hepatic lymphocytes, tumour-infiltrating lymphocytes and peripheral blood mononuclear cell analysis. RESULTS The median overall survival was 19.2 months. Tumour tissue analysis revealed enhanced interferon responses, with stronger effects in responders. Gene set variation analysis indicated enhanced antigen presentation in responders. Spatial analysis revealed that non-responder tumours had higher numbers of Tregs located in neighbourhoods enriched with immune cells and expressed higher levels of ICOS and PD-1. Conversely, non-responder PD1+CD8+T in these Treg-enriched neighbourhoods expressed lower ICOS. Cell-communication analysis demonstrated that Treg-CD8+T interaction was enhanced in non-responder tissue. Peripheral blood analysis showed increased classical monocytes in responders and Tregs in non-responders. Treg-CD8+T interaction was confirmed in preclinical models. Finally, single-patient computational analysis from the all-across analysis was performed on 860 features, which led to the identification of multiomics feature sets including Treg features. CONCLUSION Our study provides a blueprint for in-depth analysis of immune correlates in immunotherapy studies and demonstrates the importance of Treg distribution in HCC. TRIAL REGISTRATION NUMBERS NCT02821754 and the EudraCT identifier: 2019-002767-98.
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Affiliation(s)
- Yuta Myojin
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Sepideh Babaei
- Interfaculty Institute for Biomedical Informatics (IBMI), University of Tübingen, Tubingen, Germany
- Department of Internal Medicine I (Gastroenterology, Gastrointestinal Oncology, Hepatology, Infectious Diseases and Geriatrics), University Hospital Tübingen, Tübingen, Germany
- M3 Research Center, University Hospital Tübingen, Tübingen, Germany
| | - Rajiv Trehan
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Christoph Hoffman
- Interfaculty Institute for Biomedical Informatics (IBMI), University of Tübingen, Tubingen, Germany
- Department of Internal Medicine I (Gastroenterology, Gastrointestinal Oncology, Hepatology, Infectious Diseases and Geriatrics), University Hospital Tübingen, Tübingen, Germany
- M3 Research Center, University Hospital Tübingen, Tübingen, Germany
| | - Noemi Kedei
- Collaborative Protein Technology Resources, Office of Science and Technology Resources, National Institutes of Health, Bethesda, Maryland, USA
| | - Benjamin Ruf
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- Department of Internal Medicine I (Gastroenterology, Gastrointestinal Oncology, Hepatology, Infectious Diseases and Geriatrics), University Hospital Tübingen, Tübingen, Germany
- M3 Research Center, University Hospital Tübingen, Tübingen, Germany
| | - Mohamed-Reda Benmebarek
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Kylynda C Bauer
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Patrick Huang
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Chi Ma
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Cecilia Monge
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Changqing Xie
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Donna Hrones
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Austin G Duffy
- Mater Misericordiae University Hospital, Dublin, Ireland
| | - Paul Armstrong
- Mater Misericordiae University Hospital, Dublin, Ireland
| | - Lorenz Kocheise
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Fiona Desmond
- Mater Misericordiae University Hospital, Dublin, Ireland
| | | | - Marie Galligan
- Clinical Research Centre, University College Dublin, Dublin, Ireland
| | - Colin Cantwell
- St Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Ronan Ryan
- St Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Jeff McCann
- St Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Michele Bourke
- St Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Ross Mac Nicholas
- St Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Ray McDermott
- St Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Joy Awosika
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Maggie Cam
- Center for Collaborative Bioinformatics, National Institutes of Health, Bethesda, Maryland, USA
| | - Rosanna Krebs
- Interfaculty Institute for Biomedical Informatics (IBMI), University of Tübingen, Tubingen, Germany
- Department of Internal Medicine I (Gastroenterology, Gastrointestinal Oncology, Hepatology, Infectious Diseases and Geriatrics), University Hospital Tübingen, Tübingen, Germany
- M3 Research Center, University Hospital Tübingen, Tübingen, Germany
| | - Anuradha Budhu
- Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Mahler Revsine
- Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - William D Figg
- Genitourinary Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - David E Kleiner
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Bernadette Redd
- Radiology and Imaging Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Bradford J Wood
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- Radiology and Imaging Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- Center for Interventional Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Firouzeh Korangy
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Manfred Claassen
- Interfaculty Institute for Biomedical Informatics (IBMI), University of Tübingen, Tubingen, Germany
- Department of Internal Medicine I (Gastroenterology, Gastrointestinal Oncology, Hepatology, Infectious Diseases and Geriatrics), University Hospital Tübingen, Tübingen, Germany
- M3 Research Center, University Hospital Tübingen, Tübingen, Germany
| | - Tim F Greten
- Gastrointestinal Malignancies Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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Zheng J, Wang S, Xia L, Sun Z, Chan KM, Bernards R, Qin W, Chen J, Xia Q, Jin H. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther 2025; 10:35. [PMID: 39915447 PMCID: PMC11802921 DOI: 10.1038/s41392-024-02075-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/18/2024] [Accepted: 11/14/2024] [Indexed: 02/09/2025] Open
Abstract
Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.
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Affiliation(s)
- Jiaojiao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Siying Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Lei Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Zhen Sun
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Kui Ming Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China
| | - René Bernards
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jinhong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, PR China.
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| | - Haojie Jin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
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Hermán-Sánchez N, Del Rio-Moreno M, Ciria R, Sánchez-Frias ME, Fernández-Barrena MG, Uriarte I, Chicano-Galvez E, Ortea I, Peralbo-Molina Á, Briceño J, Avila MA, Rodríguez-Perálvarez M, Luque RM, López-Cánovas JL, Gahete MD. Quantitative proteomic analysis unveils a critical role of VARS1 in hepatocellular carcinoma aggressiveness through the modulation of MAGI1 expression. Mol Cancer 2025; 24:15. [PMID: 39810176 PMCID: PMC11731432 DOI: 10.1186/s12943-024-02206-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 12/24/2024] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) genetic/transcriptomic signatures have been widely described. However, its proteomic characterization is incomplete. We performed non-targeted quantitative proteomics of HCC samples and explored its clinical, functional, and molecular consequences. METHODS Non-targeted quantitative proteomics were performed on cytosolic and nuclear fractions of liver samples [HCC vs. non-tumour adjacent tissue (NTAT), n = 42 patients]. Changes were confirmed in 7 in silico HCC cohorts. Functional and molecular implications were evaluated on HCC-derived cell lines after silencing/overexpressing VARS1 and/or MAGI1. VARS1-overexpressing Hep3B cells were used for in vivo studies [Extreme Limiting Dilution Assay (ELDA) and orthotopic tumour formation]. Quantitative proteomics were performed on VARS1-overexpressing HCC cell lines. RESULTS Quantitative proteomics revealed the dysregulation of the cytosolic and nuclear proteomes in HCC, and defined two proteomic HCC subgroups, the most aggressive associated to the dysregulation of the aminoacyl-tRNA synthetases (ARSs). ARSs dysregulation was corroborated in in silico HCC cohorts and associated to poor prognosis. Patients with ARSs upregulation had genomic/transcriptomic characteristics of the proliferative HCC. Valine tRNA-aminoacyl synthetase (VARS1) was the ARSs most consistently overexpressed and associated to aggressiveness. VARS1 modulation (silencing/overexpression) altered tumour establishment-associated parameters in vitro and/or in vivo. Quantitative proteomics on cells overexpressing VARS1 and rescue experiments identified the downregulation of MAGI1, a tumour suppressor in HCC, as a mediator of VARS1 function. CONCLUSIONS Quantitative proteomics defines two prognosis-related proteomic HCC subgroups. ARSs machinery is dysregulated in the aggressive subgroup, bearing potential as prognostic biomarkers. VARS1 promotes aggressiveness through the modulation of MAGI1, representing a novel targetable vulnerability in HCC.
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Affiliation(s)
- Natalia Hermán-Sánchez
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Reina Sofía University Hospital, Córdoba, 14004, Spain
| | - Mercedes Del Rio-Moreno
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Reina Sofía University Hospital, Córdoba, 14004, Spain
| | - Rubén Ciria
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Reina Sofía University Hospital, Córdoba, 14004, Spain
- Unit of Hepatobiliary Surgery and Liver Transplantation, Reina Sofía University Hospital, Córdoba, 14004, Spain
| | - Marina E Sánchez-Frias
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Reina Sofía University Hospital, Córdoba, 14004, Spain
- Anatomical Pathology Department, Reina Sofía University Hospital, Córdoba, 14004, Spain
| | - Maite G Fernández-Barrena
- Hepatology Laboratory, Solid Tumors Program, CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), CIMA, University of Navarra, Instituto de Salud Carlos III, Pamplona, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - Iker Uriarte
- Hepatology Laboratory, Solid Tumors Program, CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), CIMA, University of Navarra, Instituto de Salud Carlos III, Pamplona, Spain
| | - Eduardo Chicano-Galvez
- IMIBIC Mass Spectrometry and Molecular Imaging Unit (IMSMI), Reina Sofía University Hospital, Maimónides Biomedical Research Institute of Córdoba (IMIBIC), University of Córdoba (UCO), Cordoba, 14004, Spain
| | - Ignacio Ortea
- Centro de Investigación en Nanomateriales y Nanotecnología (CINN-CSIC), Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, 33011, Spain
| | - Ángela Peralbo-Molina
- IMIBIC Mass Spectrometry and Molecular Imaging Unit (IMSMI), Reina Sofía University Hospital, Maimónides Biomedical Research Institute of Córdoba (IMIBIC), University of Córdoba (UCO), Cordoba, 14004, Spain
| | - Javier Briceño
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Reina Sofía University Hospital, Córdoba, 14004, Spain
- Unit of Hepatobiliary Surgery and Liver Transplantation, Reina Sofía University Hospital, Córdoba, 14004, Spain
| | - Matías A Avila
- Hepatology Laboratory, Solid Tumors Program, CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), CIMA, University of Navarra, Instituto de Salud Carlos III, Pamplona, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - Manuel Rodríguez-Perálvarez
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Reina Sofía University Hospital, Córdoba, 14004, Spain
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Córdoba, 14004, Spain
| | - Raúl M Luque
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Reina Sofía University Hospital, Córdoba, 14004, Spain
| | - Juan L López-Cánovas
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Reina Sofía University Hospital, Córdoba, 14004, Spain
| | - Manuel D Gahete
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain.
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Reina Sofía University Hospital, Córdoba, 14004, Spain.
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Yang C, Xiang W, Wu Z, Li N, Xie G, Huang J, Zeng L, Yu H, Xiang B. CK19 protein expression: the best cutoff value on the prognosis and the prognosis model of hepatocellular carcinoma. BMC Cancer 2025; 25:55. [PMID: 39789507 PMCID: PMC11720332 DOI: 10.1186/s12885-024-13399-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 12/25/2024] [Indexed: 01/12/2025] Open
Abstract
BACKGROUND AND OBJECTIVE In clinical practice, CK19 can be an important predictor for the prognosis of HCC. Due to the high incidence and mortality rates of HCC, more effective and practical prognostic prediction models need to be developed urgently. METHODS A total of 1,168 HCC patients, who underwent radical surgery at the Guangxi Medical University Cancer Hospital, between January 2014 and July 2019, were recruited, and their clinicopathological data were collected. Among the clinicopathological data, the optimal cutoff value of CK19-positive HCC was determined by calculating the area under the curve (AUC) using survival analysis and time-dependent receiver operating characteristic (timeROC) curve analysis. The predictors were screened using univariate and multivariate COX regression and least absolute shrinkage and selection operator (LASSO) regression to construct nomogram prediction models, and their predictive potentials were assessed using calibration curves and AUC values. RESULTS The 0% positive rate of CK19 was considered the optimal cutoff value to predict the poor prognosis of CK19-positive HCC. The survival analysis of 335 CK19-positive HCC showed no significant statistical differences in the overall survival (OS) and disease-free survival (DFS) of CK19-positive HCC patients. A five-factor risk (CK19, CA125, Edmondson, BMI, and tumor number) scoring model and an OS nomograph model were constructed and established, and the OS nomograph model showed a good predictive performance and was subsequently verified. CONCLUSION A 0% expression level of CK19 protein may be an optimal threshold for predicting the prognosis of CK19-positive HCC. Based on this, CK19 marker a good nomogram model was constructed to predict HCC prognosis.
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Affiliation(s)
- Chenglei Yang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Province, 530021, China
- Guangxi Hepatocellular Carcinoma Diagnosis and Treatment Engineering Technology Research Center, Nanning, Guangxi Province, 530021, China
- Regional Key Laboratory for Early Prevention and Treatment of High Incidence Tumor, Ministry of Education, Nanning, Guangxi Province, 530021, China
| | - Wanyan Xiang
- The First Clinical Medical College of Guangxi Medical University, Nanning, Guangxi Province, 530021, China
| | - Zongze Wu
- The First Clinical Medical College of Guangxi Medical University, Nanning, Guangxi Province, 530021, China
| | - Nannan Li
- Department of Ultrasound, Guangxi Zhuang Autonomous Region Workers' Hospital, Nanning, Guangxi Province, 530021, China
| | - Guoliang Xie
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Province, 530021, China
- Guangxi Hepatocellular Carcinoma Diagnosis and Treatment Engineering Technology Research Center, Nanning, Guangxi Province, 530021, China
- Regional Key Laboratory for Early Prevention and Treatment of High Incidence Tumor, Ministry of Education, Nanning, Guangxi Province, 530021, China
| | - Juntao Huang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Province, 530021, China
- Guangxi Hepatocellular Carcinoma Diagnosis and Treatment Engineering Technology Research Center, Nanning, Guangxi Province, 530021, China
- Regional Key Laboratory for Early Prevention and Treatment of High Incidence Tumor, Ministry of Education, Nanning, Guangxi Province, 530021, China
| | - Lixia Zeng
- Department of Pathology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Province, 530021, China
| | - Hongping Yu
- Regional Key Laboratory for Early Prevention and Treatment of High Incidence Tumor, Ministry of Education, Nanning, Guangxi Province, 530021, China.
- Tumor Prevention and Control Office, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Province, 530021, China.
| | - Bangde Xiang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Province, 530021, China.
- Guangxi Hepatocellular Carcinoma Diagnosis and Treatment Engineering Technology Research Center, Nanning, Guangxi Province, 530021, China.
- Regional Key Laboratory for Early Prevention and Treatment of High Incidence Tumor, Ministry of Education, Nanning, Guangxi Province, 530021, China.
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Wang Z, Chen C, Ai J, Gao Y, Wang L, Xia S, Jia Y, Qin Y. The crosstalk between senescence, tumor, and immunity: molecular mechanism and therapeutic opportunities. MedComm (Beijing) 2025; 6:e70048. [PMID: 39811803 PMCID: PMC11731108 DOI: 10.1002/mco2.70048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 11/30/2024] [Accepted: 12/10/2024] [Indexed: 01/16/2025] Open
Abstract
Cellular senescence is characterized by a stable cell cycle arrest and a hypersecretory, proinflammatory phenotype in response to various stress stimuli. Traditionally, this state has been viewed as a tumor-suppressing mechanism that prevents the proliferation of damaged cells while activating the immune response for their clearance. However, senescence is increasingly recognized as a contributing factor to tumor progression. This dual role necessitates a careful evaluation of the beneficial and detrimental aspects of senescence within the tumor microenvironment (TME). Specifically, senescent cells display a unique senescence-associated secretory phenotype that releases a diverse array of soluble factors affecting the TME. Furthermore, the impact of senescence on tumor-immune interaction is complex and often underappreciated. Senescent immune cells create an immunosuppressive TME favoring tumor progression. In contrast, senescent tumor cells could promote a transition from immune evasion to clearance. Given these intricate dynamics, therapies targeting senescence hold promise for advancing antitumor strategies. This review aims to summarize the dual effects of senescence on tumor progression, explore its influence on tumor-immune interactions, and discuss potential therapeutic strategies, alongside challenges and future directions. Understanding how senescence regulates antitumor immunity, along with new therapeutic interventions, is essential for managing tumor cell senescence and remodeling the immune microenvironment.
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Affiliation(s)
- Zehua Wang
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Chen Chen
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Jiaoyu Ai
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Yaping Gao
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Lei Wang
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Shurui Xia
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Yongxu Jia
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Yanru Qin
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
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10
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Lan B, Luo C, Pocha C, Wang Q, Tan J. Comparison of various liver cancer staging systems in predicting prognosis after initial transcatheter arterial chemoembolization: a retrospective study from China. J Gastrointest Oncol 2024; 15:2599-2612. [PMID: 39816009 PMCID: PMC11732340 DOI: 10.21037/jgo-2024-850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 12/13/2024] [Indexed: 01/18/2025] Open
Abstract
Background Hepatocellular carcinoma (HCC) constitutes approximately 75-85% of primary liver cancers and is a heavy burden on public health. Many innovative prediction systems have integrated radiomics, artificial intelligence, pathological information, or even genetic information for the stratification and prognosis prediction of patients with HCC. However, these systems still lack practical and clinical applications. Classical HCC staging systems remain the mainstream tool for stratification and prediction of treatment efficacy to date; although, variable characteristics and emphases between different classical HCC staging systems render its clinical selection inconsistent and therefore may be unreliable. In this study, we aimed to compare the predictive performance of classical liver cancer staging systems, including China Liver Cancer (CNLC), Barcelona Clinic Liver Cancer (BCLC), Hong Kong Liver Cancer (HKLC), modified Japanese Integrated Staging (mJIS), modified Cancer of the Liver Italian Program (mCLIP), and Tumor-Node-Metastasis (TNM) staging system, for the efficacy and prognosis of transcatheter arterial chemoembolization (TACE) in HCC patients. Methods A total of 148 patients with HCC who received TACE as the initial therapy between 02/01/2019 and 08/31/2022 were retrospectively included. Patients' clinical information, laboratory and imaging data, were collected. Cox regression analysis was applied to identify independent risk factors for progression-free survival (PFS) and overall survival (OS). Six liver cancer staging systems, including the CNLC, BCLC, HKLC, mJIS, mCLIP, and TNM staging system, were applied for the staging of every enrolled patient. The PFS and OS of patients with HCC following initial TACE in different staging systems were assessed, and the predictive performance of different systems was evaluated using the concordance index. Results The presence of portal vein tumor thrombus (PVT), alpha fetoprotein (AFP) ≥400 ng/mL, and ineffective initial TACE treatment were independent risk factors for overall disease progression, while the presence of PVT and ineffective initial TACE treatment were independent risk factors for death. In the prediction of PFS and OS, CNLC, BCLC, HKLC, mJIS, and mCLIP all showed good predictive ability, but the predictive ability of the TNM staging system was relatively poor. Conclusions The CNLC, BCLC, HKLC, mJIS, and mCLIP staging systems provide comparable predictive value for the prognosis after the initial TACE, while the TNM staging system has poor predictive ability due to its exclusion of hepatic function.
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Affiliation(s)
- Bin Lan
- Department of Interventional Vascular Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, China
| | - Chao Luo
- Department of Interventional Vascular Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, China
| | - Christine Pocha
- Avera Hepatology and Transplant Institute, University of South Dakota, Sioux Falls, SD, USA
| | - Qing Wang
- Department of Interventional Vascular Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, China
| | - Jie Tan
- Department of Interventional Vascular Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, China
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11
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Dantzer C, Dif L, Vaché J, Basbous S, Billottet C, Moreau V. Specific features of ß-catenin-mutated hepatocellular carcinomas. Br J Cancer 2024; 131:1871-1880. [PMID: 39261716 PMCID: PMC11628615 DOI: 10.1038/s41416-024-02849-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/26/2024] [Accepted: 09/02/2024] [Indexed: 09/13/2024] Open
Abstract
CTNNB1, encoding the ß-catenin protein, is a key oncogene contributing to liver carcinogenesis. Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer in adult, representing the third leading cause of cancer-related death. Aberrant activation of the Wnt/ß-catenin pathway, mainly due to mutations of the CTNNB1 gene, is observed in a significant subset of HCC. In this review, we first resume the major recent advances in HCC classification with a focus on CTNNB1-mutated HCC subclass. We present the regulatory mechanisms involved in β-catenin stabilisation, transcriptional activity and binding to partner proteins. We then describe specific phenotypic characteristics of CTNNB1-mutated HCC thanks to their unique gene expression patterns. CTNNB1-mutated HCC constitute a full-fledged subclass of HCC with distinct pathological features such as well-differentiated cells with low proliferation rate, association to cholestasis, metabolic alterations, immune exclusion and invasion. Finally, we discuss therapeutic approaches to target ß-catenin-mutated liver tumours and innovative perspectives for future drug developments.
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Affiliation(s)
| | - Lydia Dif
- University Bordeaux, INSERM, BRIC, U1312, Bordeaux, France
| | - Justine Vaché
- University Bordeaux, INSERM, BRIC, U1312, Bordeaux, France
| | - Sara Basbous
- University Bordeaux, INSERM, BRIC, U1312, Bordeaux, France
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12
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Das D, Wang X, Chiu YC, Bouamar H, Sharkey FE, Lopera JE, Lai Z, Weintraub ST, Han X, Zou Y, Chen HIH, Zeballos Torrez CR, Gu X, Cserhati M, Michalek JE, Halff GA, Chen Y, Zheng S, Cigarroa FG, Sun LZ. Integrative multi-omics characterization of hepatocellular carcinoma in Hispanic patients. J Natl Cancer Inst 2024; 116:1961-1978. [PMID: 39189979 PMCID: PMC11630563 DOI: 10.1093/jnci/djae207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 07/23/2024] [Accepted: 08/20/2024] [Indexed: 08/28/2024] Open
Abstract
BACKGROUND The incidence and mortality rates of hepatocellular carcinoma among Hispanic individuals in the United States are much higher than in non-Hispanic White people. We conducted multi-omics analyses to elucidate molecular alterations in hepatocellular carcinoma among Hispanic patients. METHODS Paired tumor and adjacent nontumor samples were collected from 31 Hispanic hepatocellular carcinomas in South Texas for genomic, transcriptomic, proteomic, and metabolomic profiling. Serum lipids were profiled in 40 Hispanic and non-Hispanic patients with or without clinically diagnosed hepatocellular carcinoma. RESULTS Exome sequencing revealed high mutation frequencies of AXIN2 and CTNNB1 in South Texas Hispanic hepatocellular carcinoma patients, suggesting a predominant activation of the Wnt/β-catenin pathway. TERT promoter mutations were also statistically significantly more frequent in the Hispanic cohort (Fisher exact test, P < .05). Cell cycles and liver function were positively and negatively enriched, respectively, with gene set enrichment analysis. Gene sets representing specific liver metabolic pathways were associated with dysregulation of corresponding metabolites. Negative enrichment of liver adipogenesis and lipid metabolism corroborated with a significant reduction in most lipids in serum samples of hepatocellular carcinoma patients (paired t test, P < .0001). Two hepatocellular carcinoma subtypes from our Hispanic cohort were identified and validated with the Cancer Genome Atlas liver cancer cohort. Patients with better overall survival showed higher activity of immune and angiogenesis signatures and lower activity of liver function-related gene signatures. They also had higher levels of immune checkpoint and immune exhaustion markers. CONCLUSIONS Our study revealed specific molecular features of Hispanic hepatocellular carcinoma and potential biomarkers for therapeutic management. It provides a unique resource for studying Hispanic hepatocellular carcinoma.
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Affiliation(s)
- Debodipta Das
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Xiaojing Wang
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Department of Population Health Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Yu-Chiao Chiu
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Hakim Bouamar
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Francis E Sharkey
- Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Jorge E Lopera
- Department of Radiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Zhao Lai
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Susan T Weintraub
- Department of Biochemistry & Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Xianlin Han
- Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Yi Zou
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Hung-I H Chen
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Carla R Zeballos Torrez
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Xiang Gu
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Matyas Cserhati
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Joel E Michalek
- Department of Population Health Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Glenn A Halff
- Transplant Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Yidong Chen
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Department of Population Health Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Siyuan Zheng
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Department of Population Health Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Francisco G Cigarroa
- Transplant Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Lu-Zhe Sun
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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13
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Lehrich BM, Tao J, Liu S, Hirsch TZ, Yasaka TM, Cao C, Delgado ER, Guan X, Lu S, Pan L, Liu Y, Singh S, Poddar M, Bell A, Singhi AD, Zucman-Rossi J, Wang Y, Monga SP. Development of mutated β-catenin gene signature to identify CTNNB1 mutations from whole and spatial transcriptomic data in patients with HCC. JHEP Rep 2024; 6:101186. [PMID: 39583094 PMCID: PMC11582745 DOI: 10.1016/j.jhepr.2024.101186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 07/26/2024] [Accepted: 08/05/2024] [Indexed: 11/26/2024] Open
Abstract
Background & Aims Patients with β-catenin (encoded by CTNNB1)-mutated hepatocellular carcinoma (HCC) demonstrate heterogenous responses to first-line immune checkpoint inhibitors (ICIs). Precision-medicine based treatments for this subclass are currently in clinical development. Here, we report derivation of the Mutated β-catenin Gene Signature (MBGS) to predict CTNNB1-mutational status in patients with HCC for future application in personalized medicine treatment regimens. Methods Co-expression of mutant-Nrf2 and hMet ± mutant-β-catenin in murine livers in mice led to HCC development. The MBGS was derived using bulk RNA-seq and intersectional transcriptomic analysis of β-catenin-mutated and non-mutated HCC models. Integrated RNA/whole-exome-sequencing and spatial transcriptomic data from multiple cohorts of patients with HCC was assessed to address the ability of MBGS to detect CTNNB1 mutation, the tumor immune microenvironment, and/or predict therapeutic responses. Results Bulk RNA-seq comparing HCC specimens in mutant β-catenin-Nrf2, β-catenin-Met and β-catenin-Nrf2-Met to Nrf2-Met HCC model yielded 95 common upregulated genes. In The Cancer Genome Atlas (TCGA)-LIHC dataset, differential gene expression analysis with false discovery rate (FDR) = 0.05 and log2(fold change) >1.5 on the 95 common genes comparing CTNNB1-mutated vs. wild-type patients narrowed the gene panel to a 13-gene MBGS. MBGS predicted CTNNB1-mutations in TCGA (n = 374) and French (n = 398) patient cohorts with AUCs of 0.90 and 0.94, respectively. Additionally, a higher MBGS expression score was associated with lack of significant improvement in overall survival or progression-free survival in the atezolizumab-bevacizumab arm vs. the sorafenib arm in the IMbrave150 cohort. MBGS performed comparable or superior to other CTNNB1-mutant classifiers. MBGS overlapped with Hoshida S3, Boyault G5/G6, and Chiang CTNNB1 subclass tumors in TCGA and in HCC spatial transcriptomic datasets visually depicting these tumors to be situated in an immune excluded tumor microenvironment. Conclusions MBGS will aid in patient stratification to guide precision medicine therapeutics for CTNNB1-mutated HCC subclass as a companion diagnostic, as anti-β-catenin therapies become available. Impact and implications As precision medicine for liver cancer treatment becomes a reality, diagnostic tools are needed to help classify patients into groups for the best treatment choices. We have developed a molecular signature that could serve as a companion diagnostic and uses bulk or spatial transcriptomic data to identify a unique subclass of liver tumors. This subgroup of liver cancer patients derive limited benefit from the current standard of care and are expected to benefit from specialized directed therapies that are on the horizon.
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Affiliation(s)
- Brandon M. Lehrich
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- Medical Scientist Training Program, University of Pittsburgh, Pittsburgh, PA, USA
| | - Junyan Tao
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Silvia Liu
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Theo Z. Hirsch
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, Paris, France
- Institut du Cancer Paris CARPEM, AP-HP, Department of Oncology, Hopital Européen Georges Pompidou, Paris, France
| | - Tyler M. Yasaka
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- Medical Scientist Training Program, University of Pittsburgh, Pittsburgh, PA, USA
| | - Catherine Cao
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Evan R. Delgado
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Xiangnan Guan
- Translational Medicine, Genentech Inc., San Francisco, CA, USA
| | - Shan Lu
- Translational Medicine, Genentech Inc., San Francisco, CA, USA
| | - Long Pan
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, Paris, France
- Institut du Cancer Paris CARPEM, AP-HP, Department of Oncology, Hopital Européen Georges Pompidou, Paris, France
| | - Yuqing Liu
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Sucha Singh
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Minakshi Poddar
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Aaron Bell
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Aatur D. Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, Paris, France
- Institut du Cancer Paris CARPEM, AP-HP, Department of Oncology, Hopital Européen Georges Pompidou, Paris, France
| | - Yulei Wang
- Translational Medicine, Genentech Inc., San Francisco, CA, USA
| | - Satdarshan P. Monga
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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14
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Pan J, Zhang C, Huang H, Zhu Y, Zhang Y, Wu S, Zhao YC, Chen F. Deciphering the Prognostic and Therapeutic Value of a Gene Model Associated with Two Aggressive Hepatocellular Carcinoma Phenotypes Using Machine Learning. J Hepatocell Carcinoma 2024; 11:2373-2390. [PMID: 39634327 PMCID: PMC11614714 DOI: 10.2147/jhc.s480358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 11/19/2024] [Indexed: 12/07/2024] Open
Abstract
Background Macrotrabecular-massive (MTM) and vessels encapsulating tumor clusters (VETC)-hepatocellular carcinoma (HCC) are aggressive histopathological phenotypes with significant prognostic implications. However, the molecular markers associated with MTM-HCC and VETC-HCC and their implications for clinical outcomes and therapeutic strategies remain unclear. Methods Utilizing the TCGA-LIHC cohort, we employed machine learning techniques to develop a prognostic risk score based on MTM and VETC-related genes. The performance of the risk score was assessed by investigating various aspects including clinical outcomes, biological pathways, treatment responses, drug sensitivities, tumor microenvironment, and molecular subclasses. To validate the risk score, additional data from the ICGC-JP, GSE14520, GSE104580, GSE109211, and an in-house cohort were collected and analyzed. Results The machine learning algorithm established a 4-gene-based risk score. High-risk patients had significantly worse prognosis compared to low-risk patients, with the risk score being associated with malignant progression of HCC. Functionally, the high-risk group exhibited enrichment in tumor proliferation pathways. Additionally, patients in the low-risk group exhibited improved response to TACE and sorafenib treatments compared to the high-risk group. In contrast, the high-risk group exhibited reduced sensitivity to immunotherapy and increased sensitivity to paclitaxel. In the in-house cohort, high-risk patients displayed higher rates of early recurrence, along with an increased frequency of elevated alpha-fetoprotein, microvascular invasion, and aggressive MRI features associated with HCC. Conclusion This study has successfully developed a risk score based on MTM and VETC-related genes, providing a promising tool for prognosis prediction and personalized treatment strategies in HCC patients.
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Affiliation(s)
- Junhan Pan
- Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Cong Zhang
- Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Huizhen Huang
- Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Yanyan Zhu
- Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Yuhao Zhang
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Shuzhen Wu
- Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Yan-Ci Zhao
- Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Feng Chen
- Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
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15
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López CL, Calvo M, Cámara JC, García-Paredes B, Gómez-Martin C, López AM, Pazo-Cid R, Sastre J, Yaya R, Feliu J. SEOM-GEMCAD-TTD clinical guidelines for the management of hepatocarcinoma patients (2023). Clin Transl Oncol 2024; 26:2800-2811. [PMID: 38914756 PMCID: PMC11467113 DOI: 10.1007/s12094-024-03568-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/11/2024] [Indexed: 06/26/2024]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy in the liver and is the third cause of cancer-related death worldwide. Surveillance with abdominal ultrasound should be offered to individuals at high risk for developing HCC. Accurate diagnosis, staging, and liver function are crucial when determining the optimal therapeutic approach. The BCLC staging system is widely endorsed in Western countries. Managing this pathology requires a multidisciplinary, personalized approach, generally with a multimodal strategy. Surgery remains the only curative option, albeit local and systemic therapy may also increase survival when surgery is not suitable. In advanced disease, systemic treatment should be offered to patients with ECOG/PS 0-1 and Child-Pugh class A.
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Affiliation(s)
- Carlos López López
- Medical Oncology Department, H. U. Marqués de Valdecilla, IDIVAL, UNICAN, Santander, Cantabria, Spain.
| | - Mariona Calvo
- Medical Oncology Department, Institut Català d'Oncologia-L'Hospitalet del Llobregat, Barcelona, Spain
| | - Juan Carlos Cámara
- Medical Oncology Department, Hospital Universitario Fundación Alcorcón, Madrid, Spain
| | | | - Carlos Gómez-Martin
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
| | - Ana María López
- Medical Oncology Department, Hospital Universitario de Burgos, Burgos, Spain
| | - Roberto Pazo-Cid
- Medical Oncology Department, Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Javier Sastre
- Medical Oncology Department, Hospital Universitario Clínico San Carlos, Madrid, Spain
| | - Ricardo Yaya
- Medical Oncology Department, Instituvo Valenciano de Oncología, Valencia, Spain
| | - Jaime Feliu
- Medical Oncology Department, Hospital Universitario de La Paz, IdiPAZ, CIBERONC, UAM, Madrid, Spain
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16
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Piqué-Gili M, Andreu-Oller C, Mesropian A, Esteban-Fabró R, Bárcena-Varela M, Ruiz de Galarreta M, Montironi C, Martinez-Quetglas I, Cappuyns S, Peix J, Keraite I, Gris-Oliver A, Fernández-Martínez E, Mauro E, Torres-Martin M, Abril-Fornaguera J, Lindblad KE, Lambrechts D, Dekervel J, Thung SN, Sia D, Lujambio A, Pinyol R, Llovet JM. Oncogenic role of PMEPA1 and its association with immune exhaustion and TGF-β activation in HCC. JHEP Rep 2024; 6:101212. [PMID: 39524206 PMCID: PMC11550205 DOI: 10.1016/j.jhepr.2024.101212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 08/16/2024] [Accepted: 08/30/2024] [Indexed: 11/16/2024] Open
Abstract
Background & Aims Transforming growth factor β (TGF-β) plays an oncogenic role in advanced cancer by promoting cell proliferation, metastasis and immunosuppression. PMEPA1 (prostate transmembrane protein androgen induced 1) has been shown to promote TGF-β oncogenic effects in other tumour types. Thus, we aimed to explore the role of PMEPA1 in hepatocellular carcinoma (HCC). Methods We analysed 1,097 tumours from patients with HCC, including discovery (n = 228) and validation (n = 361) cohorts with genomic and clinicopathological data. PMEPA1 levels were assessed by qPCR (n = 228), gene expression data (n = 869) and at the single-cell level (n = 54). Genetically engineered mouse models overexpressing MYC+PMEPA1 compared to MYC were generated and molecular analyses were performed on the HCCs obtained. Results PMEPA1 was overexpressed in 18% of HCC samples (fold-change >2; n = 201/1,097), a feature associated with TGF-β signalling activation (p <0.05) and absence of gene body hypomethylation (p <0.01). HCCs showing both TGF-β signalling and high PMEPA1 levels (12% of cases) were linked to immune exhaustion, late TGF-β activation, aggressiveness and higher recurrence rates after resection, in contrast to HCCs with only TGF-β signalling (8%) or PMEPA1 overexpression (9%). Single-cell RNA sequencing analysis identified PMEPA1 expression in HCC and stromal cells. PMEPA1-expressing tumoural cells were predicted to interact with CD4+ regulatory T cells and CD4+ CXCL13+ and CD8+ exhausted T cells. In vivo, overexpression of MYC+PMEPA1 led to HCC development in ∼60% of mice and a decreased survival compared to mice overexpressing MYC alone (p = 0.014). MYC+PMEPA1 tumours were enriched in TGF-β signalling, paralleling our human data. Conclusions In human HCC, PMEPA1 upregulation is linked to TGF-β activation, immune exhaustion, and an aggressive phenotype. Overexpression of PMEPA1+MYC led to tumoural development in vivo, demonstrating the oncogenic role of PMEPA1 in HCC for the first time. Impact and implications PMEPA1 can enhance the tumour-promoting effects of TGF-β in cancer. In this study, we demonstrate that PMEPA1 is highly expressed in ∼18% of patients with hepatocellular carcinoma (HCC), a feature associated with poor prognosis, TGF-β activation and exhaustion of immune cells. Similarly, in mouse models, PMEPA1 overexpression promotes HCC development, which demonstrates its oncogenic role. The identification of PMEPA1 as oncogenic driver in HCC and its role in immune exhaustion and poor clinical outcomes enhances our understanding of HCC pathogenesis and opens new avenues for targeted therapeutic interventions.
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Affiliation(s)
- Marta Piqué-Gili
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Carmen Andreu-Oller
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Agavni Mesropian
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Roger Esteban-Fabró
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Marina Bárcena-Varela
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Marina Ruiz de Galarreta
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Carla Montironi
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
- Pathology Department & Molecular Biology CORE, Biomedical Diagnostic Center, Barcelona Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
| | - Iris Martinez-Quetglas
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Sarah Cappuyns
- Digestive Oncology, Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium
- Laboratory of Clinical Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium
- Laboratory for Translational Genetics, Department of Human Genetics, VIB and KU Leuven, Leuven, Belgium
- VIB Centre for Cancer Biology, Leuven, Belgium
| | - Judit Peix
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Ieva Keraite
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Albert Gris-Oliver
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Elisa Fernández-Martínez
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Ezequiel Mauro
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Miguel Torres-Martin
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Jordi Abril-Fornaguera
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Katherine E. Lindblad
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Diether Lambrechts
- Laboratory for Translational Genetics, Department of Human Genetics, VIB and KU Leuven, Leuven, Belgium
- VIB Centre for Cancer Biology, Leuven, Belgium
| | - Jeroen Dekervel
- Digestive Oncology, Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium
- Laboratory of Clinical Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Swan N. Thung
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Daniela Sia
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Amaia Lujambio
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Roser Pinyol
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Josep M. Llovet
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
- Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain
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17
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Cao WH, Zhang YQ, Li XX, Zhang ZY, Li MH. Advances in immunotherapy for hepatitis B virus associated hepatocellular carcinoma patients. World J Hepatol 2024; 16:1158-1168. [PMID: 39474576 PMCID: PMC11514615 DOI: 10.4254/wjh.v16.i10.1158] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/28/2024] [Accepted: 09/19/2024] [Indexed: 10/21/2024] Open
Abstract
Hepatitis B virus (HBV) infection plays an important role in the occurrence and development of hepatocellular carcinoma (HCC), and the rate of HBV infection in liver cancer patients in China is as high as 92.05%. Due to long-term exposure to chronic antigens from the gut, the liver needs to maintain a certain level of immune tolerance, both to avoid severe inflammation caused by non-pathogenic antigens and to maintain the possibility of rapid and violent responses to infection and tumors. Therefore, HBV infection interacts with the tumor microenvironment (TME) through a highly complex and intertwined signaling pathway, which results in a special TME in HCC. Due to changes in the TME, tumor cells can evade immune surveillance by inhibiting tumor-specific T cell function through cytotoxic T-lymphocy-associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1). Interferons, as a class of immune factors with strong biological activity, can improve the TME of HBV-HCC through various pathways. In recent years, the systematic treatment of HCC has gradually come out of the dilemma. In addition to the continuous emergence of new multi-target anti-vascular tyrosine kinase inhibitor drugs, immune checkpoint inhibitors have opened up a new avenue for the systematic treatment of HCC. At present, immunotherapy based on PD-1/L1 inhibitors has gradually become a new direction of systematic treatment for HCC, and the disease characteristics of patients included in global clinical studies are different from those of Chinese patients. Therefore, whether a group of HCC patients with HBV background and poor prognosis in China can also benefit from immunotherapy is an issue of wide concern. This review aims to elucidate the advances of immunotherapy for HBV related HCC patients with regard to: (1) Immunotherapy based on interferons; (2) Immunotherapy based on PD-1/L1 inhibitors; (3) Immunotherapy based on CTLA4 inhibitors; (4) Adoptive cell transfer; (5) Combination immunotherapy strategy; and (6) Shortcomings of immunotherapy.
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Affiliation(s)
- Wei-Hua Cao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ya-Qin Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xin-Xin Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Zi-Yu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ming-Hui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Peking University Ditan Teaching Hospital, Beijing 100015, China
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18
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Cao WH, Zhang YQ, Li XX, Zhang ZY, Li MH. Advances in immunotherapy for hepatitis B virus associated hepatocellular carcinoma patients. World J Hepatol 2024; 16:1338-1348. [DOI: 10.4254/wjh.v16.i10.1338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/28/2024] [Accepted: 09/19/2024] [Indexed: 11/22/2024] Open
Abstract
Hepatitis B virus (HBV) infection plays an important role in the occurrence and development of hepatocellular carcinoma (HCC), and the rate of HBV infection in liver cancer patients in China is as high as 92.05%. Due to long-term exposure to chronic antigens from the gut, the liver needs to maintain a certain level of immune tolerance, both to avoid severe inflammation caused by non-pathogenic antigens and to maintain the possibility of rapid and violent responses to infection and tumors. Therefore, HBV infection interacts with the tumor microenvironment (TME) through a highly complex and intertwined signaling pathway, which results in a special TME in HCC. Due to changes in the TME, tumor cells can evade immune surveillance by inhibiting tumor-specific T cell function through cytotoxic T-lymphocy-associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1). Interferons, as a class of immune factors with strong biological activity, can improve the TME of HBV-HCC through various pathways. In recent years, the systematic treatment of HCC has gradually come out of the dilemma. In addition to the continuous emergence of new multi-target anti-vascular tyrosine kinase inhibitor drugs, immune checkpoint inhibitors have opened up a new avenue for the systematic treatment of HCC. At present, immunotherapy based on PD-1/L1 inhibitors has gradually become a new direction of systematic treatment for HCC, and the disease characteristics of patients included in global clinical studies are different from those of Chinese patients. Therefore, whether a group of HCC patients with HBV background and poor prognosis in China can also benefit from immunotherapy is an issue of wide concern. This review aims to elucidate the advances of immunotherapy for HBV related HCC patients with regard to: (1) Immunotherapy based on interferons; (2) Immunotherapy based on PD-1/L1 inhibitors; (3) Immunotherapy based on CTLA4 inhibitors; (4) Adoptive cell transfer; (5) Combination immunotherapy strategy; and (6) Shortcomings of immunotherapy.
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Affiliation(s)
- Wei-Hua Cao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ya-Qin Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xin-Xin Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Zi-Yu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ming-Hui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Peking University Ditan Teaching Hospital, Beijing 100015, China
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Nassar KM, Yang X, Baker A, Gopalam R, Arnold WC, Adeniran TT, Hernandez Fernandez MH, Mahajan M, Lai Z, Chen Y, Sareddy GR, Viswanadhapalli S, Sun LZ, Vadlamudi RK, Pratap UP. PELP1 Is a Novel Therapeutic Target in Hepatocellular Carcinoma. CANCER RESEARCH COMMUNICATIONS 2024; 4:2610-2620. [PMID: 39258975 PMCID: PMC11456993 DOI: 10.1158/2767-9764.crc-24-0173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 07/31/2024] [Accepted: 09/05/2024] [Indexed: 09/12/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the United States, with a median survival period of approximately 10 months. There is an urgent need for the development of effective targeted therapies for the treatment of HCC. Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) signaling is implicated in the progression of many cancers, although its specific contribution to the progression of HCC is not yet well understood. Analysis of The Cancer Genome Atlas HCC gene expression data sets and IHC analysis of HCC tissue microarray revealed that HCC tumors had elevated expression of PELP1 compared with normal tissues, and high expression of PELP1 is associated with unfavorable survival outcomes. Suppression of PELP1 expression using short hairpin RNA significantly reduced the cell viability, clonogenicity, and invasion of HCC cells. Importantly, SMIP34, a first-in-class small-molecule inhibitor targeting PELP1, effectively decreased the cell viability, clonogenic survival, and invasiveness of HCC cells. Gene expression analysis using RNA sequencing revealed that PELP1 knockdown cells exhibited a decrease in c-Myc, E2F, and other oncogenic pathways related to HCC. Mechanistic studies showed that SMIP34 treatment impaired the Rix complex, a critical component of ribosomal biogenesis, in HCC cells. Furthermore, the knockdown or pharmacologic inhibition of PELP1 significantly decelerated the HCC tumor growth in xenograft models. In summary, our study findings indicate that PELP1 could serve as a promising target for therapeutic intervention in HCC. SIGNIFICANCE HCC is one of the leading causes of cancer fatalities in the United States. Effective targeted therapeutics for HCC are urgently needed. In this study, we show that PELP1 proto-oncogene is crucial to HCC progression and that PELP1 inhibition reduced HCC cell proliferation in vitro and in vivo. Our results imply that PELP1-targeted drugs like SMIP34 may be useful as new therapeutic agents for HCC treatment.
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Affiliation(s)
- Khaled Mohamed Nassar
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
| | - Xue Yang
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
| | - Adriana Baker
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
| | - Rahul Gopalam
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
| | - William C. Arnold
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
| | - Timilehin T. Adeniran
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
| | | | - Megharani Mahajan
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
| | - Zhao Lai
- Greehey Children’s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, Texas.
- Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, Texas.
| | - Yidong Chen
- Greehey Children’s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, Texas.
- Department of Population Health Sciences, University of Texas Health San Antonio, San Antonio, Texas.
| | - Gangadhara R. Sareddy
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, Texas.
| | - Suryavathi Viswanadhapalli
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, Texas.
| | - Lu-Zhe Sun
- Department of Cell Systems & Anatomy, University of Texas Health San Antonio, San Antonio, Texas.
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, Texas.
| | - Ratna K. Vadlamudi
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, Texas.
- Audie L. Murphy South Texas Veterans Health Care System, San Antonio, Texas.
| | - Uday P. Pratap
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, Texas.
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20
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Qiu X, Zhou T, Li S, Wu J, Tang J, Ma G, Yang S, Hu J, Wang K, Shen S, Wang H, Chen L. Spatial single-cell protein landscape reveals vimentin high macrophages as immune-suppressive in the microenvironment of hepatocellular carcinoma. NATURE CANCER 2024; 5:1557-1578. [PMID: 39327501 DOI: 10.1038/s43018-024-00824-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 08/09/2024] [Indexed: 09/28/2024]
Abstract
Tumor microenvironment heterogeneity in hepatocellular carcinoma (HCC) on a spatial single-cell resolution is unclear. Here, we conducted co-detection by indexing to profile the spatial heterogeneity of 401 HCC samples with 36 biomarkers. By parsing the spatial tumor ecosystem of liver cancer, we identified spatial patterns with distinct prognosis and genomic and molecular features, and unveiled the progressive role of vimentin (VIM)high macrophages. Integration analysis with eight independent cohorts demonstrated that the spatial co-occurrence of VIMhigh macrophages and regulatory T cells promotes tumor progression and favors immunotherapy. Functional studies further demonstrated that VIMhigh macrophages enhance the immune-suppressive activity of regulatory T cells by mechanistically increasing the secretion of interleukin-1β. Our data provide deep insights into the heterogeneity of tumor microenvironment architecture and unveil the critical role of VIMhigh macrophages during HCC progression, which holds potential for personalized cancer prevention and drug discovery and reinforces the need to resolve spatial-informed features for cancer treatment.
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Affiliation(s)
- Xinyao Qiu
- Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Tao Zhou
- National Center for Liver Cancer, Shanghai, China
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Shuai Li
- Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China
| | - Jianmin Wu
- Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China
| | - Jing Tang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guosheng Ma
- Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China
| | - Shuai Yang
- Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ji Hu
- National Center for Liver Cancer, Shanghai, China
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Kaiting Wang
- Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China
| | - Siyun Shen
- National Center for Liver Cancer, Shanghai, China
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Hongyang Wang
- Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
- Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, China.
- Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, China.
| | - Lei Chen
- Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- National Center for Liver Cancer, Shanghai, China.
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, China.
- Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, China.
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21
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Deng Q, Huang Y, Zeng J, Li X, Zheng X, Guo L, Shi J, Bai L. Recent advancements in the small-molecule drugs for hepatocellular carcinoma (HCC): Structure-activity relationships, pharmacological activities, and the clinical trials. Biomed Pharmacother 2024; 179:117343. [PMID: 39180795 DOI: 10.1016/j.biopha.2024.117343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 08/14/2024] [Accepted: 08/21/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world and the sixth leading cause of cancer death worldwide, and it is urgent to find safe and effective drugs for treatment. As an important therapeutic method, small-molecule drugs are continually being updated to achieve improved therapeutic effects. The purpose of this study was to investigate the structural effects of various FDA-listed small-molecule drugs sorafenib, cabozantinib, lenvatinib, and regorafenib on the corresponding HCC targets and possible structural optimization methods, and to explore the mechanism for identifying potential therapeutic drugs that offer better efficacy and fewer side effects. METHODS The structure-activity relationship, pharmacological actions, and clinical applications of small-molecule drugs were reviewed by referencing MEDLINE, Web of Science, CNKI, and other databases, summarizing and integrating the relevant content. RESULTS The results showed that small-molecule drugs can inhibit HCC primarily by forming hydrogen bonds with Glu885, Asp1046, and Cys919 on the HCC target. HCC can be targeted by inhibiting the activation of multiple pathways, blocking the conduction of downstream signaling, and reducing the formation of tumor blood vessels. In general, small-molecule drugs primarily target four key receptors in HCC: VEGFR, PDGFR, EGFR, and FGFR, to achieve effective treatment. CONCLUSIONS By revealing their structure-activity relationships, pharmacological actions, and clinical trials, small-molecule drugs can offer broad prospects for the development of new medications.
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Affiliation(s)
- Qichuan Deng
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yu Huang
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, China
| | - Jing Zeng
- School of Food and Bioengineering, Xihua University, Chengdu, Sichuan 610039, China
| | - Xinyu Li
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xianyi Zheng
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Li Guo
- The State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
| | - Jianyou Shi
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
| | - Lan Bai
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China; The State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
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22
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Chen J, Kaya NA, Zhang Y, Kendarsari RI, Sekar K, Lee Chong S, Seshachalam VP, Ling WH, Jin Phua CZ, Lai H, Yang H, Lu B, Lim JQ, Ma S, Chew SC, Chua KP, Santiago Alvarez JJ, Wu L, Ooi L, Yaw-Fui Chung A, Cheow PC, Kam JH, Wei-Chieh Kow A, Ganpathi IS, Bunchaliew C, Thammasiri J, Koh PS, Bee-Lan Ong D, Lim J, de Villa VH, Dela Cruz RD, Loh TJ, Wan WK, Leow WQ, Yang Y, Liu J, Skanderup AJ, Pang YH, Ting Soon GS, Madhavan K, Kiat-Hon Lim T, Bonney G, Goh BKP, Chew V, Dan YY, Toh HC, Sik-Yin Foo R, Tam WL, Zhai W, Kah-Hoe Chow P. A multimodal atlas of hepatocellular carcinoma reveals convergent evolutionary paths and 'bad apple' effect on clinical trajectory. J Hepatol 2024; 81:667-678. [PMID: 38782118 DOI: 10.1016/j.jhep.2024.05.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 05/06/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is a highly fatal cancer characterized by high intra-tumor heterogeneity (ITH). A panoramic understanding of its tumor evolution, in relation to its clinical trajectory, may provide novel prognostic and treatment strategies. METHODS Through the Asia-Pacific Hepatocellular Carcinoma trials group (NCT03267641), we recruited one of the largest prospective cohorts of patients with HCC, with over 600 whole genome and transcriptome samples from 123 treatment-naïve patients. RESULTS Using a multi-region sampling approach, we revealed seven convergent genetic evolutionary paths governed by the early driver mutations, late copy number variations and viral integrations, which stratify patient clinical trajectories after surgical resection. Furthermore, such evolutionary paths shaped the molecular profiles, leading to distinct transcriptomic subtypes. Most significantly, although we found the coexistence of multiple transcriptomic subtypes within certain tumors, patient prognosis was best predicted by the most aggressive cell fraction of the tumor, rather than by overall degree of transcriptomic ITH level - a phenomenon we termed the 'bad apple' effect. Finally, we found that characteristics throughout early and late tumor evolution provide significant and complementary prognostic power in predicting patient survival. CONCLUSIONS Taken together, our study generated a comprehensive landscape of evolutionary history for HCC and provides a rich multi-omics resource for understanding tumor heterogeneity and clinical trajectories. IMPACT AND IMPLICATIONS This prospective study, utilizing comprehensive multi-sector, multi-omics sequencing and clinical data from surgically resected hepatocellular carcinoma (HCC), reveals critical insights into the role of tumor evolution and intra-tumor heterogeneity (ITH) in determining the prognosis of HCC. These findings are invaluable for oncology researchers and clinicians, as they underscore the influence of distinct evolutionary paths and the 'bad apple' effect, where the most aggressive tumor fraction dictates disease progression. These insights not only enhance prognostic accuracy post-surgical resection but also pave the way for personalized treatment strategies tailored to specific tumor evolutionary and transcriptomic profiles. The coexistence of multiple subtypes within the same tumor prompts a re-appraisal of the utilities of depending on single samples to represent the entire tumor and suggests the need for clinical molecular imaging. This research thus marks a significant step forward in the clinical understanding and management of HCC, underscoring the importance of integrating tumor evolutionary dynamics and multi-omics biomarkers into therapeutic decision-making. CLINICAL TRIAL NUMBER NCT03267641 (Observational cohort).
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Affiliation(s)
- Jianbin Chen
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore.
| | - Neslihan Arife Kaya
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore; School of Biological Sciences, Nanyang Technological University, Singapore 637551, Republic of Singapore
| | - Ying Zhang
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore
| | - Raden Indah Kendarsari
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore
| | - Karthik Sekar
- Program in Clinical and Translational Liver Cancer Research, Division of Medical Science, National Cancer Center Singapore, Republic of Singapore
| | - Shay Lee Chong
- Program in Clinical and Translational Liver Cancer Research, Division of Medical Science, National Cancer Center Singapore, Republic of Singapore
| | - Veerabrahma Pratap Seshachalam
- Program in Clinical and Translational Liver Cancer Research, Division of Medical Science, National Cancer Center Singapore, Republic of Singapore
| | - Wen Huan Ling
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore; Program in Clinical and Translational Liver Cancer Research, Division of Medical Science, National Cancer Center Singapore, Republic of Singapore
| | - Cheryl Zi Jin Phua
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore
| | - Hannah Lai
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore
| | - Hechuan Yang
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore; Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, P.R. China
| | - Bingxin Lu
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore; Cell & Developmental Biology, Division of Biosciences, Faculty of Life Sciences, Bloomsbury, London WC1E 6AP, UK
| | - Jia Qi Lim
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore
| | - Siming Ma
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore
| | - Sin Chi Chew
- Program in Clinical and Translational Liver Cancer Research, Division of Medical Science, National Cancer Center Singapore, Republic of Singapore
| | - Khi Pin Chua
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore
| | - Jacob Josiah Santiago Alvarez
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore
| | - Lingyan Wu
- Program in Clinical and Translational Liver Cancer Research, Division of Medical Science, National Cancer Center Singapore, Republic of Singapore
| | - London Ooi
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Republic of Singapore
| | - Alexander Yaw-Fui Chung
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Republic of Singapore
| | - Peng Chung Cheow
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Republic of Singapore
| | - Juinn Huar Kam
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Republic of Singapore
| | - Alfred Wei-Chieh Kow
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, University Surgical Cluster, National University Health System, Singapore 119228, Republic of Singapore
| | - Iyer Shridhar Ganpathi
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, University Surgical Cluster, National University Health System, Singapore 119228, Republic of Singapore
| | - Chairat Bunchaliew
- Hepato-Pancreato-Biliary Surgery Unit, Department of Surgery, National Cancer Institute, Bangkok, Thailand
| | | | - Peng Soon Koh
- Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Diana Bee-Lan Ong
- Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Jasmine Lim
- Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Vanessa H de Villa
- Department of Surgery and Center for Liver Disease Management and Transplantation, The Medical City, Pasig City, Metro Manila, Philippines
| | | | - Tracy Jiezhen Loh
- Department of Pathology, Singapore General Hospital, Singapore 169608, Republic of Singapore
| | - Wei Keat Wan
- Department of Pathology, Singapore General Hospital, Singapore 169608, Republic of Singapore
| | - Wei Qiang Leow
- Department of Pathology, Singapore General Hospital, Singapore 169608, Republic of Singapore
| | - Yi Yang
- School of Data Science, The Chinese University of Hong Kong-Shenzhen, Shenzhen 518172, China
| | - Jin Liu
- School of Data Science, The Chinese University of Hong Kong-Shenzhen, Shenzhen 518172, China
| | - Anders Jacobsen Skanderup
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore
| | - Yin Huei Pang
- Department of Pathology, National University Health System, Singapore 119074, Republic of Singapore
| | - Gwyneth Shook Ting Soon
- Department of Pathology, National University Health System, Singapore 119074, Republic of Singapore
| | - Krishnakumar Madhavan
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, University Surgical Cluster, National University Health System, Singapore 119228, Republic of Singapore
| | - Tony Kiat-Hon Lim
- Department of Pathology, Singapore General Hospital, Singapore 169608, Republic of Singapore
| | - Glenn Bonney
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, University Surgical Cluster, National University Health System, Singapore 119228, Republic of Singapore
| | - Brian K P Goh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Republic of Singapore
| | - Valerie Chew
- Translational Immunology Institute (TII), SingHealth Duke-NUS Academic Medical Centre, Singapore, Republic of Singapore
| | - Yock Young Dan
- Division of Gastroenterology and Hepatology, University Medicine Cluster, National University Hospital, Singapore, Republic of Singapore
| | - Han Chong Toh
- Division of Medical Oncology, National Cancer Center Singapore, 169610 Singapore, Republic of Singapore
| | - Roger Sik-Yin Foo
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore; Cardiovascular Research Institute, National University of Singapore, National University Healthcare System, Singapore 119228, Republic of Singapore
| | - Wai Leong Tam
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Republic of Singapore; Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599, Republic of Singapore; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University Singapore, 14 Medical Drive, Singapore 117599, Republic of Singapore.
| | - Weiwei Zhai
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore; Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, P.R. China; Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, P.R. China.
| | - Pierce Kah-Hoe Chow
- Program in Clinical and Translational Liver Cancer Research, Division of Medical Science, National Cancer Center Singapore, Republic of Singapore; Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Republic of Singapore; SingHealth-Duke-NUS Academic Surgery Program, Duke-NUS Graduate Medical School, Singapore 169857, Republic of Singapore.
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23
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Jin Z, Wang X, Zhang X, Cheng S, Liu Y. Identification of two heterogeneous subtypes of hepatocellular carcinoma with distinct pathway activities and clinical outcomes based on gene set variation analysis. Front Genet 2024; 15:1441189. [PMID: 39323867 PMCID: PMC11423295 DOI: 10.3389/fgene.2024.1441189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 08/26/2024] [Indexed: 09/27/2024] Open
Abstract
Background High heterogeneity is an essential feature of malignant tumors. This study aims to reveal the drivers of hepatocellular carcinoma heterogeneity for prognostic stratification and to guide individualized treatment. Methods Omics data and clinical data for two HCC cohorts were derived from the Cancer Genome Atlas (TCGA) and the International Cancer Genome Atlas (ICGC), respectively. CNV data and methylation data were downloaded from the GSCA database. GSVA was used to estimate the transcriptional activity of KEGG pathways, and consensus clustering was used to categorize the HCC samples. The pRRophetic package was used to predict the sensitivity of samples to anticancer drugs. TIMER, MCPcounter, quanTIseq, and TIDE algorithms were used to assess the components of TME. LASSO and COX analyses were used to establish a prognostic gene signature. The biological role played by genes in HCC cells was confirmed by in vitro experiments. Results We classified HCC tissues into two categories based on the activity of prognostic pathways. Among them, the transcriptional profile of cluster A HCC is similar to that of normal tissue, dominated by cancer-suppressive metabolic pathways, and has a better prognosis. In contrast, cluster B HCC is dominated by high proliferative activity and has significant genetic heterogeneity. Meanwhile, cluster B HCC is often poorly differentiated, has a high rate of serum AFP positivity, is prone to microvascular invasion, and has shorter overall survival. In addition, we found that mutations, copy number variations, and aberrant methylation were also crucial drivers of the differences in heterogeneity between the two HCC subtypes. Meanwhile, the TME of the two HCC subtypes is also significantly different, which offers the possibility of precision immunotherapy for HCC patients. Finally, based on the prognostic value of molecular subtypes, we developed a gene signature that could accurately predict patients' OS. The riskscore quantified by the signature could evaluate the heterogeneity of HCC and guide clinical treatment. Finally, we confirmed through in vitro experiments that RFPL4B could promote the progression of Huh7 cells. Conclusion The molecular subtypes we identified effectively exposed the heterogeneity of HCC, which is important for discovering new effective therapeutic targets.
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Affiliation(s)
- Zhipeng Jin
- Department of Hepatopancreatobiliary Surgery, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Xin Wang
- Department of Hepatopancreatobiliary Surgery, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Xue Zhang
- Central Laboratory, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Siqi Cheng
- Department of Hepatopancreatobiliary Surgery, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Yefu Liu
- Department of Hepatopancreatobiliary Surgery, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
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24
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Sun Z, Liu H, Zhao Q, Li JH, Peng SF, Zhang Z, Yang JH, Fu Y. Immune-related cell death index and its application for hepatocellular carcinoma. NPJ Precis Oncol 2024; 8:194. [PMID: 39245753 PMCID: PMC11381516 DOI: 10.1038/s41698-024-00693-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 08/28/2024] [Indexed: 09/10/2024] Open
Abstract
Regulated cell death (RCD) plays a crucial role in the immune microenvironment, development, and progression of hepatocellular carcinoma (HCC). However, reliable immune-related cell death signatures have not been explored. In this study, we collected 12 RCD modes (e.g., apoptosis, ferroptosis, and cuproptosis), including 1078 regulators, to identify immune-related cell death genes based on HCC immune subgroups. Using a developed competitive machine learning framework, nine genes were screened to construct the immune-related cell death index (IRCDI), which is available for online application. Multi-omics data, along with clinical features, were analyzed to explore the HCC malignant heterogeneity. To validate the efficacy of this model, more than 18 independent cohorts, including survival and diverse treatment cohorts and datasets, were utilized. These findings were further validated using in-house samples and molecular biological experiments. Overall, the IRCDI may have a wide application in individual therapeutic decision-making and improving outcomes for HCC patients.
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Affiliation(s)
- Zhao Sun
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Hao Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Qian Zhao
- Clinical Systems Biology Key Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jie-Han Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - San-Fei Peng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhen Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jing-Hua Yang
- Clinical Systems Biology Key Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| | - Yang Fu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
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25
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Macdonald JK, Taylor HB, Wang M, Delacourt A, Edge C, Lewin DN, Kubota N, Fujiwara N, Rasha F, Marquez CA, Ono A, Oka S, Chayama K, Lewis S, Taouli B, Schwartz M, Fiel MI, Drake RR, Hoshida Y, Mehta AS, Angel PM. The Spatial Extracellular Proteomic Tumor Microenvironment Distinguishes Molecular Subtypes of Hepatocellular Carcinoma. J Proteome Res 2024; 23:3791-3805. [PMID: 38980715 PMCID: PMC11385377 DOI: 10.1021/acs.jproteome.4c00099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 05/31/2024] [Accepted: 06/15/2024] [Indexed: 07/10/2024]
Abstract
Hepatocellular carcinoma (HCC) mortality rates continue to increase faster than those of other cancer types due to high heterogeneity, which limits diagnosis and treatment. Pathological and molecular subtyping have identified that HCC tumors with poor outcomes are characterized by intratumoral collagenous accumulation. However, the translational and post-translational regulation of tumor collagen, which is critical to the outcome, remains largely unknown. Here, we investigate the spatial extracellular proteome to understand the differences associated with HCC tumors defined by Hoshida transcriptomic subtypes of poor outcome (Subtype 1; S1; n = 12) and better outcome (Subtype 3; S3; n = 24) that show differential stroma-regulated pathways. Collagen-targeted mass spectrometry imaging (MSI) with the same-tissue reference libraries, built from untargeted and targeted LC-MS/MS was used to spatially define the extracellular microenvironment from clinically-characterized, formalin-fixed, paraffin-embedded tissue sections. Collagen α-1(I) chain domains for discoidin-domain receptor and integrin binding showed distinctive spatial distribution within the tumor microenvironment. Hydroxylated proline (HYP)-containing peptides from the triple helical regions of fibrillar collagens distinguished S1 from S3 tumors. Exploratory machine learning on multiple peptides extracted from the tumor regions could distinguish S1 and S3 tumors (with an area under the receiver operating curve of ≥0.98; 95% confidence intervals between 0.976 and 1.00; and accuracies above 94%). An overall finding was that the extracellular microenvironment has a high potential to predict clinically relevant outcomes in HCC.
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Affiliation(s)
- Jade K. Macdonald
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Harrison B. Taylor
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Mengjun Wang
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Andrew Delacourt
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Christin Edge
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - David N. Lewin
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Naoto Kubota
- Liver
Tumor Translational Research Program, Simmons Comprehensive Cancer
Center, Division of Digestive and Liver Diseases, Department of Internal
Medicine, University of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
| | - Naoto Fujiwara
- Liver
Tumor Translational Research Program, Simmons Comprehensive Cancer
Center, Division of Digestive and Liver Diseases, Department of Internal
Medicine, University of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
| | - Fahmida Rasha
- Liver
Tumor Translational Research Program, Simmons Comprehensive Cancer
Center, Division of Digestive and Liver Diseases, Department of Internal
Medicine, University of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
| | - Cesia A. Marquez
- Liver
Tumor Translational Research Program, Simmons Comprehensive Cancer
Center, Division of Digestive and Liver Diseases, Department of Internal
Medicine, University of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
| | - Atsushi Ono
- Department
of Gastroenterology, Graduate School of
Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan
| | - Shiro Oka
- Department
of Gastroenterology, Graduate School of
Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan
| | - Kazuaki Chayama
- Hiroshima
Institute of Life Sciences, Hiroshima 734-8553, Japan
- Collaborative
Research Laboratory of Medical Innovation, Research Center for Hepatology
and Gastroenterology, Hiroshima University, Hiroshima 734-8553, Japan
- RIKEN Center
for Integrative Medical Sciences, Yokohama 230-0045, Japan
| | - Sara Lewis
- Department
of Radiology, Icahn School of Medicine at
Mount Sinai, New York, New York 10029, United States
| | - Bachir Taouli
- Department
of Radiology, Icahn School of Medicine at
Mount Sinai, New York, New York 10029, United States
| | - Myron Schwartz
- Department
of Radiology, Icahn School of Medicine at
Mount Sinai, New York, New York 10029, United States
- Department
of Surgery, Icahn School of Medicine at
Mount Sinai, New York, New York 10029, United States
| | - M Isabel Fiel
- Department
of Radiology, Icahn School of Medicine at
Mount Sinai, New York, New York 10029, United States
- Department
of Pathology, Icahn School of Medicine at
Mount Sinai, New York, New York 10029, United States
| | - Richard R. Drake
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Yujin Hoshida
- Liver
Tumor Translational Research Program, Simmons Comprehensive Cancer
Center, Division of Digestive and Liver Diseases, Department of Internal
Medicine, University of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
| | - Anand S. Mehta
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Peggi M. Angel
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
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26
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Wang X, Yang Y, Zhao S, Wu D, Li L, Zhao Z. Chitosan-based biomaterial delivery strategies for hepatocellular carcinoma. Front Pharmacol 2024; 15:1446030. [PMID: 39161903 PMCID: PMC11330802 DOI: 10.3389/fphar.2024.1446030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Accepted: 07/23/2024] [Indexed: 08/21/2024] Open
Abstract
Background Hepatocellular carcinoma accounts for 80% of primary liver cancers, is the most common primary liver malignancy. Hepatocellular carcinoma is the third leading cause of tumor-related deaths worldwide, with a 5-year survival rate of approximately 18%. Chemotherapy, although commonly used for hepatocellular carcinoma treatment, is limited by systemic toxicity and drug resistance. Improving targeted delivery of chemotherapy drugs to tumor cells without causing systemic side effects is a current research focus. Chitosan, a biopolymer derived from chitin, possesses good biocompatibility and biodegradability, making it suitable for drug delivery. Enhanced chitosan formulations retain the anti-tumor properties while improving stability. Chitosan-based biomaterials promote hepatocellular carcinoma apoptosis, exhibit antioxidant and anti-inflammatory effects, inhibit tumor angiogenesis, and improve extracellular matrix remodeling for enhanced anti-tumor therapy. Methods We summarized published experimental papers by querying them. Results and Conclusions This review discusses the physicochemical properties of chitosan, its application in hepatocellular carcinoma treatment, and the challenges faced by chitosan-based biomaterials.
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Affiliation(s)
- Xianling Wang
- Department of Gastroenterology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Yan Yang
- Department of Gastroenterology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Shuang Zhao
- Endoscopy Center, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Di Wu
- First Digestive Endoscopy Department, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Le Li
- Department of Gastroenterology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhifeng Zhao
- Department of Gastroenterology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
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27
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Oshi M, Chida K, Roy AM, Mann GK, An N, Yan L, Endo I, Takabe K. Higher inflammatory response in hepatocellular carcinoma is associated with immune cell infiltration and a better outcome. Hepatol Int 2024; 18:1299-1309. [PMID: 38898190 DOI: 10.1007/s12072-024-10678-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 04/01/2024] [Indexed: 06/21/2024]
Abstract
BACKGROUND AND AIMS Hepatocellular carcinoma (HCC) often develops from chronic liver inflammation. Inflammation within a tumor can either promote cancer progression or activate an immune response against it. This study aims to determine the clinical significance of enhanced inflammation in HCC. METHODS Data from 655 HCC patients across four cohorts (TCGA, GSE6764, GSE76427, GSE89377) were examined. Inflammatory response was quantified using a scoring system derived from the gene set variation analysis of the "INFLAMMATORY_RESPONSE" gene set. RESULTS A stepwise increase in inflammatory response was noted from normal liver to cirrhosis, with consistently lower levels in HCC across both GSE6764 and GSE89377 cohorts (both p < 0.001). Similar trends were observed in interferon response, pathways such as IL6/JAK/STAT3 and complement signaling, coagulation cascade, and allograft rejection (all p < 0.02). HCCs with high inflammatory response were associated with increased immune cell infiltrations (p < 0.01) and cytolytic activity (p < 0.001). Interestingly, these HCCs had reduced mutation rates, no relationship with cell proliferation, and displayed both immune responses and pro-cancerous signals including epithelial-mesenchymal transition, KRAS, and hypoxia. Further, a high inflammatory score correlated with improved disease-free survival in TCGA (p = 0.034) and overall survival in GSE76427 (p = 0.008). CONCLUSION HCC with higher levels of inflammatory response demonstrated increased immune cell infiltration, enhanced immune-related and other pro-cancerous-related signaling, and showed a trend toward a better patient prognosis.
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Affiliation(s)
- Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan
| | - Kohei Chida
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Arya Mariam Roy
- Department of Hematology and Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Gabriella Kim Mann
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Nan An
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, 160-8402, Japan.
- Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, Yokohama, Kanagawa, Japan.
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan.
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8520, Japan.
- Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan.
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY, 14263, USA.
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28
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Sundi PRIO, Thipe VC, Omar MA, Adelusi TI, Gedefa J, Olaoba OT. Preclinical human and murine models of hepatocellular carcinoma (HCC). Clin Res Hepatol Gastroenterol 2024; 48:102418. [PMID: 39004339 DOI: 10.1016/j.clinre.2024.102418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 05/17/2024] [Accepted: 07/04/2024] [Indexed: 07/16/2024]
Abstract
Hepatocellular carcinoma (HCC) is the most frequent liver cancer, which account for more than 90 % of all liver cancer cases. It is the fifth leading cause of cancer globally and the second leading cause of cancer-related mortality in men. The availability of competent HCC preclinical models is fundamental to the success of mechanistic studies, molecular target identification, and drug testing. However, there are challenges associated with the use of these models. In this review, we provided updates on various cell lines, animals, and human HCC models, their specific preclinic use and associated potential challenges. Overall, the understanding of the merits and demerits of a particular HCC model will improve model selection for various preclinical studies.
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Affiliation(s)
- Pharidah Rajan Ibrahim Omar Sundi
- Lusaka Apex Medical University, Off Mumbwa Road, Lusaka 10101, Zambia; Pan African Organization for Health, Education and Research (POHER), United States
| | - Velaphi C Thipe
- Department of Radiology, Institute of Green Nanotechnology and Cancer Nanotechnology, University of Missouri, Columbia, MO 65211, USA
| | | | | | - Jalene Gedefa
- Collage of Health Sciences, Addis Ababa University, Ethiopia
| | - Olamide T Olaoba
- Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65211, USA.
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29
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Amadeo E, Foti S, Camera S, Rossari F, Persano M, Lo Prinzi F, Vitiello F, Casadei-Gardini A, Rimini M. Developing targeted therapeutics for hepatocellular carcinoma: a critical assessment of promising phase II agents. Expert Opin Investig Drugs 2024; 33:839-849. [PMID: 39039690 DOI: 10.1080/13543784.2024.2377321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 07/03/2024] [Indexed: 07/24/2024]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the first for primary liver tumors. In recent years greater therapeutic advancement was represented by employment of tyrosine kinase inhibitors (TKIs) either in monotherapy or in combination with immune checkpoint inhibitors (ICIs). AREAS COVERED Major attention was given to target therapies in the last couple of years, especially in those currently under phase II trials. Priority was given either to combinations of novel ICI and TKIs or those targeting alternative mutations of major carcinogenic pathways. EXPERT OPINION As TKIs are playing a more crucial role in HCC therapeutic strategies, it is fundamental to further expand molecular testing and monitoring of acquired resistances. Despite the recent advancement in both laboratory and clinical studies, further research is necessary to face the discrepancy in clinical practice.
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Affiliation(s)
- Elisabeth Amadeo
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Silvia Foti
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Silvia Camera
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Federico Rossari
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Mara Persano
- Medical Oncology, University and University Hospital of Cagliari, Cagliari, Italy
| | - Federica Lo Prinzi
- Operative Research Unit of Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Francesco Vitiello
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Andrea Casadei-Gardini
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Margherita Rimini
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
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30
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Barace S, Santamaría E, Infante S, Arcelus S, De La Fuente J, Goñi E, Tamayo I, Ochoa I, Sogbe M, Sangro B, Hernaez M, Avila MA, Argemi J. Application of Graph Models to the Identification of Transcriptomic Oncometabolic Pathways in Human Hepatocellular Carcinoma. Biomolecules 2024; 14:653. [PMID: 38927057 PMCID: PMC11201933 DOI: 10.3390/biom14060653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 05/22/2024] [Accepted: 05/29/2024] [Indexed: 06/28/2024] Open
Abstract
Whole-tissue transcriptomic analyses have been helpful to characterize molecular subtypes of hepatocellular carcinoma (HCC). Metabolic subtypes of human HCC have been defined, yet whether these different metabolic classes are clinically relevant or derive in actionable cancer vulnerabilities is still an unanswered question. Publicly available gene sets or gene signatures have been used to infer functional changes through gene set enrichment methods. However, metabolism-related gene signatures are poorly co-expressed when applied to a biological context. Here, we apply a simple method to infer highly consistent signatures using graph-based statistics. Using the Cancer Genome Atlas Liver Hepatocellular cohort (LIHC), we describe the main metabolic clusters and their relationship with commonly used molecular classes, and with the presence of TP53 or CTNNB1 driver mutations. We find similar results in our validation cohort, the LIRI-JP cohort. We describe how previously described metabolic subtypes could not have therapeutic relevance due to their overall downregulation when compared to non-tumoral liver, and identify N-glycan, mevalonate and sphingolipid biosynthetic pathways as the hallmark of the oncogenic shift of the use of acetyl-coenzyme A in HCC metabolism. Finally, using DepMap data, we demonstrate metabolic vulnerabilities in HCC cell lines.
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Affiliation(s)
- Sergio Barace
- DNA and RNA Medicine Division, Applied Medical Research Center (CIMA), University of Navarre, 31008 Pamplona, Spain; (S.B.); (E.S.); (S.I.); (S.A.)
| | - Eva Santamaría
- DNA and RNA Medicine Division, Applied Medical Research Center (CIMA), University of Navarre, 31008 Pamplona, Spain; (S.B.); (E.S.); (S.I.); (S.A.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-EHD), Av. Monforte de Lemos, 3-5. Pabellón 11, Planta 0, 28029 Madrid, Spain (M.A.A.)
| | - Stefany Infante
- DNA and RNA Medicine Division, Applied Medical Research Center (CIMA), University of Navarre, 31008 Pamplona, Spain; (S.B.); (E.S.); (S.I.); (S.A.)
- Facultad de Medicina Humana, Universidad de Piura, Lima 15074, Peru
| | - Sara Arcelus
- DNA and RNA Medicine Division, Applied Medical Research Center (CIMA), University of Navarre, 31008 Pamplona, Spain; (S.B.); (E.S.); (S.I.); (S.A.)
| | - Jesus De La Fuente
- Bioinformatics Platform, Applied Medical Research Center (CIMA), University of Navarre, 31008 Pamplona, Spain (M.H.)
| | - Enrique Goñi
- Bioinformatics Platform, Applied Medical Research Center (CIMA), University of Navarre, 31008 Pamplona, Spain (M.H.)
| | - Ibon Tamayo
- Bioinformatics Platform, Applied Medical Research Center (CIMA), University of Navarre, 31008 Pamplona, Spain (M.H.)
| | - Idoia Ochoa
- Tecnun School of Engineering (TECNUN), University of Navarre, 31008 Pamplona, Spain;
| | - Miguel Sogbe
- Liver Unit, Tecnun School of Engineering (TECNUN), University of Navarre, 31008 Pamplona, Spain;
| | - Bruno Sangro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-EHD), Av. Monforte de Lemos, 3-5. Pabellón 11, Planta 0, 28029 Madrid, Spain (M.A.A.)
- Liver Unit, Tecnun School of Engineering (TECNUN), University of Navarre, 31008 Pamplona, Spain;
- Instituto de Investigación Sanitaria de Navarra (IdisNA), 31008 Pamplona, Spain
| | - Mikel Hernaez
- Bioinformatics Platform, Applied Medical Research Center (CIMA), University of Navarre, 31008 Pamplona, Spain (M.H.)
- Instituto de Investigación Sanitaria de Navarra (IdisNA), 31008 Pamplona, Spain
| | - Matias A. Avila
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-EHD), Av. Monforte de Lemos, 3-5. Pabellón 11, Planta 0, 28029 Madrid, Spain (M.A.A.)
- Instituto de Investigación Sanitaria de Navarra (IdisNA), 31008 Pamplona, Spain
- Solid Tumor Program, Hepatology Laboratory, Applied Medical Research Center (CIMA), University of Navarre, C. de Irunlarrea, 3, 31008 Pamplona, Spain
| | - Josepmaria Argemi
- DNA and RNA Medicine Division, Applied Medical Research Center (CIMA), University of Navarre, 31008 Pamplona, Spain; (S.B.); (E.S.); (S.I.); (S.A.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-EHD), Av. Monforte de Lemos, 3-5. Pabellón 11, Planta 0, 28029 Madrid, Spain (M.A.A.)
- Liver Unit, Tecnun School of Engineering (TECNUN), University of Navarre, 31008 Pamplona, Spain;
- Instituto de Investigación Sanitaria de Navarra (IdisNA), 31008 Pamplona, Spain
- Division of Gastroenterology Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA 15232, USA
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31
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Xue Y, Ruan Y, Wang Y, Xiao P, Xu J. Signaling pathways in liver cancer: pathogenesis and targeted therapy. MOLECULAR BIOMEDICINE 2024; 5:20. [PMID: 38816668 PMCID: PMC11139849 DOI: 10.1186/s43556-024-00184-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 04/23/2024] [Indexed: 06/01/2024] Open
Abstract
Liver cancer remains one of the most prevalent malignancies worldwide with high incidence and mortality rates. Due to its subtle onset, liver cancer is commonly diagnosed at a late stage when surgical interventions are no longer feasible. This situation highlights the critical role of systemic treatments, including targeted therapies, in bettering patient outcomes. Despite numerous studies on the mechanisms underlying liver cancer, tyrosine kinase inhibitors (TKIs) are the only widely used clinical inhibitors, represented by sorafenib, whose clinical application is greatly limited by the phenomenon of drug resistance. Here we show an in-depth discussion of the signaling pathways frequently implicated in liver cancer pathogenesis and the inhibitors targeting these pathways under investigation or already in use in the management of advanced liver cancer. We elucidate the oncogenic roles of these pathways in liver cancer especially hepatocellular carcinoma (HCC), as well as the current state of research on inhibitors respectively. Given that TKIs represent the sole class of targeted therapeutics for liver cancer employed in clinical practice, we have particularly focused on TKIs and the mechanisms of the commonly encountered phenomena of its resistance during HCC treatment. This necessitates the imperative development of innovative targeted strategies and the urgency of overcoming the existing limitations. This review endeavors to shed light on the utilization of targeted therapy in advanced liver cancer, with a vision to improve the unsatisfactory prognostic outlook for those patients.
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Affiliation(s)
- Yangtao Xue
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Hangzhou, 310016, China
- Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Yeling Ruan
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Hangzhou, 310016, China
- Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Yali Wang
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Hangzhou, 310016, China
- Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Peng Xiao
- Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
| | - Junjie Xu
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Hangzhou, 310016, China.
- Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China.
- Zhejiang University Cancer Center, Hangzhou, 310058, China.
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China.
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32
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Feng F, Zhao Y. Hepatocellular Carcinoma: Prevention, Diagnosis, and Treatment. Med Princ Pract 2024; 33:414-423. [PMID: 38772352 PMCID: PMC11460940 DOI: 10.1159/000539349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 05/14/2024] [Indexed: 05/23/2024] Open
Abstract
Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer globally, poses a substantial health burden. Influenced by risk factors such as hepatitis B or C virus infections, chronic consumption of alcohol, and metabolic dysfunction, its exact etiology likely involves a complex interplay between viral infection, hepatocyte mutations, and chronic liver diseases like cirrhosis and metabolic dysfunction-associated steatohepatitis, and demographic variables like sex, race, and age. Disease stage significantly impacts the prognosis of HCC. There is significant potential for life-saving and socioeconomic benefits through the implementation of surveillance programs and the introduction of low-cost screening measures for high-risk groups; these screening measures include ultrasound imaging and blood tests. Treatment options for HCC encompass liver resection, transplantation, transarterial chemoembolization, radiation therapy, chemotherapy, targeted therapy, and immunotherapy. Despite therapeutic advances, treating advanced HCC remains challenging, emphasizing the need for continued efforts in prevention, early detection, and development of treatments to improve prognosis and long-term survival.
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Affiliation(s)
- Fei Feng
- Ultrasound Medicine, The First Hospital of Lanzhou University, Lanzhou, China,
| | - Yue Zhao
- Department of Gastroenterology, The First Hospital of Lanzhou University, Key Laboratory for Gastrointestinal Disease of Gansu Province, Lanzhou, China
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Zuo A, Li J, Weng S, Xu H, Zhang Y, Wang L, Xing Z, Luo P, Cheng Q, Li J, Han X, Liu Z. Integrated Exploration of Epigenetic Dysregulation Reveals a Stemness/EMT Subtype and MMP12 Linked to the Progression and Prognosis in Hepatocellular Carcinoma. J Proteome Res 2024; 23:1821-1833. [PMID: 38652053 DOI: 10.1021/acs.jproteome.4c00036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2024]
Abstract
Epigenetic dysregulation drives aberrant transcriptional programs playing a critical role in hepatocellular carcinoma (HCC), which may provide novel insights into the heterogeneity of HCC. This study performed an integrated exploration on the epigenetic dysregulation of miRNA and methylation. We discovered and validated three patterns endowed with gene-related transcriptional traits and clinical outcomes. Specially, a stemness/epithelial-mesenchymal transition (EMT) subtype was featured by immune exhaustion and the worst prognosis. Besides, MMP12, a characteristic gene, was highly expressed in the stemness/EMT subtype, which was verified as a pivotal regulator linked to the unfavorable prognosis and further proven to promote tumor proliferation, invasion, and metastasis in vitro experiments. Proteomic analysis by mass spectrometry sequencing also indicated that the overexpression of MMP12 was significantly associated with cell proliferation and adhesion. Taken together, this study unveils innovative insights into epigenetic dysregulation and identifies a stemness/EMT subtype-specific gene, MMP12, correlated with the progression and prognosis of HCC.
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Affiliation(s)
- Anning Zuo
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Jinyu Li
- Center of Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Siyuan Weng
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Hui Xu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yuyuan Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Libo Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Zhe Xing
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Jing Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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Das D, Wang X, Chiu YC, Bouamar H, Sharkey FE, Lopera JE, Lai Z, Weintraub ST, Han X, Zou Y, Chen HIH, Zeballos Torrez CR, Gu X, Cserhati M, Michalek JE, Halff GA, Chen Y, Zheng S, Cigarroa FG, Sun LZ. Integrative multi-omics characterization of hepatocellular carcinoma in Hispanic patients. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.04.27.24306447. [PMID: 38746245 PMCID: PMC11092709 DOI: 10.1101/2024.04.27.24306447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2024]
Abstract
Background The incidence and mortality rates of hepatocellular carcinoma (HCC) among Hispanics in the United States are much higher than those of non-Hispanic whites. We conducted comprehensive multi-omics analyses to understand molecular alterations in HCC among Hispanic patients. Methods Paired tumor and adjacent non-tumor samples were collected from 31 Hispanic HCC in South Texas (STX-Hispanic) for genomic, transcriptomic, proteomic, and metabolomic profiling. Additionally, serum lipids were profiled in 40 Hispanic and non-Hispanic patients with or without clinically diagnosed HCC. Results Exome sequencing revealed high mutation frequencies of AXIN2 and CTNNB1 in STX Hispanic HCCs, suggesting a predominant activation of the Wnt/β-catenin pathway. The TERT promoter mutation frequency was also remarkably high in the Hispanic cohort. Cell cycles and liver functions were identified as positively- and negatively-enriched, respectively, with gene set enrichment analysis. Gene sets representing specific liver metabolic pathways were associated with dysregulation of corresponding metabolites. Negative enrichment of liver adipogenesis and lipid metabolism corroborated with a significant reduction in most lipids in the serum samples of HCC patients. Two HCC subtypes from our Hispanic cohort were identified and validated with the TCGA liver cancer cohort. The subtype with better overall survival showed higher activity of immune and angiogenesis signatures, and lower activity of liver function-related gene signatures. It also had higher levels of immune checkpoint and immune exhaustion markers. Conclusions Our study revealed some specific molecular features of Hispanic HCC and potential biomarkers for therapeutic management of HCC and provides a unique resource for studying Hispanic HCC.
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Aguiar TFM, Rivas MP, de Andrade Silva EM, Pires SF, Dangoni GD, Macedo TC, Defelicibus A, Barros BDDF, Novak E, Cristofani LM, Odone V, Cypriano M, de Toledo SRC, da Cunha IW, da Costa CML, Carraro DM, Tojal I, de Oliveira Mendes TA, Krepischi ACV. First Transcriptome Analysis of Hepatoblastoma in Brazil: Unraveling the Pivotal Role of Noncoding RNAs and Metabolic Pathways. Biochem Genet 2024:10.1007/s10528-024-10764-y. [PMID: 38649558 DOI: 10.1007/s10528-024-10764-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 02/27/2024] [Indexed: 04/25/2024]
Abstract
Hepatoblastoma stands as the most prevalent liver cancer in the pediatric population. Characterized by a low mutational burden, chromosomal and epigenetic alterations are key drivers of its tumorigenesis. Transcriptome analysis is a powerful tool for unraveling the molecular intricacies of hepatoblastoma, shedding light on the effects of genetic and epigenetic changes on gene expression. In this study conducted in Brazilian patients, an in-depth whole transcriptome analysis was performed on 14 primary hepatoblastomas, compared to control liver tissues. The analysis unveiled 1,492 differentially expressed genes (1,031 upregulated and 461 downregulated), including 920 protein-coding genes (62%). Upregulated biological processes were linked to cell differentiation, signaling, morphogenesis, and development, involving known hepatoblastoma-associated genes (DLK1, MEG3, HDAC2, TET1, HMGA2, DKK1, DKK4), alongside with novel findings (GYNG4, CDH3, and TNFRSF19). Downregulated processes predominantly centered around oxidation and metabolism, affecting amines, nicotinamides, and lipids, featuring novel discoveries like the repression of SYT7, TTC36, THRSP, CCND1, GCK and CAMK2B. Two genes, which displayed a concordant pattern of DNA methylation alteration in their promoter regions and dysregulation in the transcriptome, were further validated by RT-qPCR: the upregulated TNFRSF19, a key gene in the embryonic development, and the repressed THRSP, connected to lipid metabolism. Furthermore, based on protein-protein interaction analysis, we identified genes holding central positions in the network, such as HDAC2, CCND1, GCK, and CAMK2B, among others, that emerged as prime candidates warranting functional validation in future studies. Notably, a significant dysregulation of non-coding RNAs (ncRNAs), predominantly upregulated transcripts, was observed, with 42% of the top 50 highly expressed genes being ncRNAs. An integrative miRNA-mRNA analysis revealed crucial biological processes associated with metabolism, oxidation reactions of lipids and carbohydrates, and methylation-dependent chromatin silencing. In particular, four upregulated miRNAs (miR-186, miR-214, miR-377, and miR-494) played a pivotal role in the network, potentially targeting multiple protein-coding transcripts, including CCND1 and CAMK2B. In summary, our transcriptome analysis highlighted disrupted embryonic development as well as metabolic pathways, particularly those involving lipids, emphasizing the emerging role of ncRNAs as epigenetic regulators in hepatoblastomas. These findings provide insights into the complexity of the hepatoblastoma transcriptome and identify potential targets for future therapeutic interventions.
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Affiliation(s)
- Talita Ferreira Marques Aguiar
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, Human Genome and Stem-Cell Research Center, University of São Paulo, São Paulo, Brazil
- Columbia University Irving Medical Center, New York, NY, USA
| | - Maria Prates Rivas
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, Human Genome and Stem-Cell Research Center, University of São Paulo, São Paulo, Brazil
| | - Edson Mario de Andrade Silva
- Department of Biochemistry and Molecular Biology, Federal University of Viçosa, Minas Gerais, Brazil
- Horticultural Sciences Department, University of Florida, Gainesville, USA
| | - Sara Ferreira Pires
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, Human Genome and Stem-Cell Research Center, University of São Paulo, São Paulo, Brazil
| | - Gustavo Dib Dangoni
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, Human Genome and Stem-Cell Research Center, University of São Paulo, São Paulo, Brazil
| | - Taiany Curdulino Macedo
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, Human Genome and Stem-Cell Research Center, University of São Paulo, São Paulo, Brazil
| | | | | | - Estela Novak
- Pediatric Cancer Institute (ITACI) at the Pediatric Department, São Paulo University Medical School, São Paulo, Brazil
| | - Lilian Maria Cristofani
- Pediatric Cancer Institute (ITACI) at the Pediatric Department, São Paulo University Medical School, São Paulo, Brazil
| | - Vicente Odone
- Pediatric Cancer Institute (ITACI) at the Pediatric Department, São Paulo University Medical School, São Paulo, Brazil
| | - Monica Cypriano
- Department of Pediatrics, Adolescent and Child With Cancer Support Group (GRAACC), Federal University of São Paulo, São Paulo, Brazil
| | - Silvia Regina Caminada de Toledo
- Department of Pediatrics, Adolescent and Child With Cancer Support Group (GRAACC), Federal University of São Paulo, São Paulo, Brazil
| | | | | | - Dirce Maria Carraro
- International Center for Research, A. C. Camargo Cancer Center, São Paulo, Brazil
| | - Israel Tojal
- International Center for Research, A. C. Camargo Cancer Center, São Paulo, Brazil
| | | | - Ana Cristina Victorino Krepischi
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, Human Genome and Stem-Cell Research Center, University of São Paulo, São Paulo, Brazil.
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Zheng S, Chan SW, Liu F, Liu J, Chow PKH, Toh HC, Hong W. Hepatocellular Carcinoma: Current Drug Therapeutic Status, Advances and Challenges. Cancers (Basel) 2024; 16:1582. [PMID: 38672664 PMCID: PMC11048862 DOI: 10.3390/cancers16081582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Revised: 04/12/2024] [Accepted: 04/19/2024] [Indexed: 04/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for ~90% of liver neoplasms. It is the second leading cause of cancer-related deaths and the seventh most common cancer worldwide. Although there have been rapid developments in the treatment of HCC over the past decade, the incidence and mortality rates of HCC remain a challenge. With the widespread use of the hepatitis B vaccine and antiviral therapy, the etiology of HCC is shifting more toward metabolic-associated steatohepatitis (MASH). Early-stage HCC can be treated with potentially curative strategies such as surgical resection, liver transplantation, and radiofrequency ablation, improving long-term survival. However, most HCC patients, when diagnosed, are already in the intermediate or advanced stages. Molecular targeted therapy, followed by immune checkpoint inhibitor immunotherapy, has been a revolution in HCC systemic treatment. Systemic treatment of HCC especially for patients with compromised liver function is still a challenge due to a significant resistance to immune checkpoint blockade, tumor heterogeneity, lack of oncogenic addiction, and lack of effective predictive and therapeutic biomarkers.
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Affiliation(s)
- Shunzhen Zheng
- Key Laboratory of Biopharmaceuticals, Postdoctoral Scientific Research Workstation, Shandong Academy of Pharmaceutical Science, Jinan 250098, China;
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Singapore 138673, Singapore; (S.W.C.); (W.H.)
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China;
| | - Siew Wee Chan
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Singapore 138673, Singapore; (S.W.C.); (W.H.)
| | - Fei Liu
- Key Laboratory of Biopharmaceuticals, Postdoctoral Scientific Research Workstation, Shandong Academy of Pharmaceutical Science, Jinan 250098, China;
| | - Jun Liu
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China;
| | - Pierce Kah Hoe Chow
- Division of Surgery and Surgical Oncology, National Cancer Centre, Singapore 169610, Singapore;
- Academic Clinical Programme for Surgery, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Han Chong Toh
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore 168583, Singapore;
| | - Wanjin Hong
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Singapore 138673, Singapore; (S.W.C.); (W.H.)
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Liu X, Zhang K, Kaya NA, Jia Z, Wu D, Chen T, Liu Z, Zhu S, Hillmer AM, Wuestefeld T, Liu J, Chan YS, Hu Z, Ma L, Jiang L, Zhai W. Tumor phylogeography reveals block-shaped spatial heterogeneity and the mode of evolution in Hepatocellular Carcinoma. Nat Commun 2024; 15:3169. [PMID: 38609353 PMCID: PMC11015015 DOI: 10.1038/s41467-024-47541-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 03/26/2024] [Indexed: 04/14/2024] Open
Abstract
Solid tumors are complex ecosystems with heterogeneous 3D structures, but the spatial intra-tumor heterogeneity (sITH) at the macroscopic (i.e., whole tumor) level is under-explored. Using a phylogeographic approach, we sequence genomes and transcriptomes from 235 spatially informed sectors across 13 hepatocellular carcinomas (HCC), generating one of the largest datasets for studying sITH. We find that tumor heterogeneity in HCC segregates into spatially variegated blocks with large genotypic and phenotypic differences. By dissecting the transcriptomic heterogeneity, we discover that 30% of patients had a "spatially competing distribution" (SCD), where different spatial blocks have distinct transcriptomic subtypes co-existing within a tumor, capturing the critical transition period in disease progression. Interestingly, the tumor regions with more advanced transcriptomic subtypes (e.g., higher cell cycle) often take clonal dominance with a wider geographic range, rejecting neutral evolution for SCD patients. Extending the statistical tests for detecting natural selection to many non-SCD patients reveal varying levels of selective signal across different tumors, implying that many evolutionary forces including natural selection and geographic isolation can influence the overall pattern of sITH. Taken together, tumor phylogeography unravels a dynamic landscape of sITH, pinpointing important evolutionary and clinical consequences of spatial heterogeneity in cancer.
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Affiliation(s)
- Xiaodong Liu
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Ke Zhang
- Department of General Surgery, Beijing Ditan Hospital, Capital Medical University, No. 8, Jingshun East Street, Chaoyang District, Beijing, P.R. China
| | - Neslihan A Kaya
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
| | - Zhe Jia
- Department of General Surgery, Beijing Ditan Hospital, Capital Medical University, No. 8, Jingshun East Street, Chaoyang District, Beijing, P.R. China
| | - Dafei Wu
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Tingting Chen
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of the Chinese Academy of Sciences, Beijing, China
| | - Zhiyuan Liu
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of the Chinese Academy of Sciences, Beijing, China
| | - Sinan Zhu
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Centre for Quantitative Medicine, Program in Health Services and Systems Research, Duke-NUS Medical School, Singapore, Singapore
| | - Axel M Hillmer
- Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Torsten Wuestefeld
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
| | - Jin Liu
- Centre for Quantitative Medicine, Program in Health Services and Systems Research, Duke-NUS Medical School, Singapore, Singapore
| | - Yun Shen Chan
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China
| | - Zheng Hu
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Liang Ma
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
| | - Li Jiang
- Department of General Surgery, Beijing Ditan Hospital, Capital Medical University, No. 8, Jingshun East Street, Chaoyang District, Beijing, P.R. China.
| | - Weiwei Zhai
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China.
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Maestri E, Kedei N, Khatib S, Forgues M, Ylaya K, Hewitt SM, Wang L, Chaisaingmongkol J, Ruchirawat M, Ma L, Wang XW. Spatial proximity of tumor-immune interactions predicts patient outcome in hepatocellular carcinoma. Hepatology 2024; 79:768-779. [PMID: 37725716 PMCID: PMC10948323 DOI: 10.1097/hep.0000000000000600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 08/30/2023] [Indexed: 09/21/2023]
Abstract
BACKGROUND AND AIMS The fitness and viability of a tumor ecosystem are influenced by the spatial organization of its cells. We aimed to study the structure, architecture, and cell-cell dynamics of the heterogeneous liver cancer tumor microenvironment using spatially resolved multiplexed imaging. APPROACH AND RESULTS We performed co-detection by indexing multiplexed immunofluorescence imaging on 68 HCC biopsies from Thai patients [(Thailand Initiative in Genomics and Expression Research for Liver Cancer (TIGER-LC)] as a discovery cohort, and then validated the results in an additional 190 HCC biopsies from Chinese patients [Liver Cancer Institute (LCI)]. We segmented and annotated 117,270 and 465,632 cells from the TIGER-LC and LCI cohorts, respectively. We observed 4 patient groups of TIGER-LC (IC1, IC2, IC3, and IC4) with distinct tumor-immune cellular interaction patterns. In addition, patients from IC2 and IC4 had much better overall survival than those from IC1 and IC3. Noticeably, tumor and CD8 + T-cell interactions were strongly enriched in IC2, the group with the best patient outcomes. The close proximity between the tumor and CD8 + T cells was a strong predictor of patient outcome in both the TIGER-LC and the LCI cohorts. Bulk transcriptomic data from 51 of the 68 HCC cases were used to determine tumor-specific gene expression features of our classified subtypes. Moreover, we observed that the presence of immune spatial neighborhoods in HCC as a measure of overall immune infiltration is linked to better patient prognosis. CONCLUSIONS Highly multiplexed imaging analysis of liver cancer reveals tumor-immune cellular heterogeneity within spatial contexts, such as tumor and CD8 + T-cell interactions, which may predict patient survival.
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Affiliation(s)
- Evan Maestri
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Noemi Kedei
- Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Subreen Khatib
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Marshonna Forgues
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Kris Ylaya
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Stephen M. Hewitt
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Limin Wang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Jittiporn Chaisaingmongkol
- Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute, Bangkok 10210, Thailand
- Center of Excellence on Environmental Health and Toxicology (EHT), OPS, MHESI, Thailand
| | - Mathuros Ruchirawat
- Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute, Bangkok 10210, Thailand
- Center of Excellence on Environmental Health and Toxicology (EHT), OPS, MHESI, Thailand
| | - Lichun Ma
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
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Chen S, Liao C, Hu H, Liao J, Chen Z, Li S, Zeng X, Peng B, Shen S, Li D, Li S, Lai J, Peng S, Xie Y, Kuang M. Hypoxia-driven tumor stromal remodeling and immunosuppressive microenvironment in scirrhous HCC. Hepatology 2024; 79:780-797. [PMID: 37725755 DOI: 10.1097/hep.0000000000000599] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 07/26/2023] [Indexed: 09/21/2023]
Abstract
BACKGROUND AND AIMS Scirrhous HCC (SHCC) is one of the unique subtypes of HCC, characterized by abundant fibrous stroma in the tumor microenvironment. However, the molecular traits of SHCC remain unclear, which is essential to develop specialized therapeutic approaches for SHCC. APPROACH AND RESULTS We presented an integrative analysis containing single-cell RNA-sequencing, whole-exome sequencing, and bulk RNA-sequencing in SHCC and usual HCC samples from 134 patients to delineate genomic features, transcriptomic profiles, and stromal immune microenvironment of SHCC. Multiplexed immunofluorescence staining, flow cytometry, and functional experiments were performed for validation. Here, we identified SHCC presented with less genomic heterogeneity while possessing a unique transcriptomic profile different from usual HCC. Insulin-like growth factor 2 was significantly upregulated in SHCC tumor cells compared to usual HCC, and could serve as a potential diagnostic biomarker for SHCC. Significant tumor stromal remodeling and hypoxia were observed in SHCC with enrichment of matrix cancer-associated fibroblasts and upregulation of hypoxic pathways. Insulin-like growth factor 2 was identified as a key mediator in shaping the hypoxic stromal microenvironment of SHCC. Under this microenvironment, SHCC exhibited an immunosuppressive niche correlated to enhanced VEGFA signaling activity, where CD4 + T cells and CD8 + T cells were dysfunctional. Furthermore, we found that another hypoxic-related molecule SPP1 from SHCC tumor cells suppressed the function of dendritic cells via the SPP1-CD44 axis, which also probably hindered the activation of T cells. CONCLUSION We uncovered the genomic characteristics of SHCC, and revealed a hypoxia-driven tumor stroma remodeling and immunosuppressive microenvironment in SHCC.
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Affiliation(s)
- Shuling Chen
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Changyi Liao
- Cancer Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Huanjing Hu
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Junbin Liao
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Zebin Chen
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Shuang Li
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Xuezhen Zeng
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Bo Peng
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Shunli Shen
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Dongming Li
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Shaoqiang Li
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Jiaming Lai
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Sui Peng
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Yubin Xie
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Ming Kuang
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
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Ramirez CFA, Taranto D, Ando-Kuri M, de Groot MHP, Tsouri E, Huang Z, de Groot D, Kluin RJC, Kloosterman DJ, Verheij J, Xu J, Vegna S, Akkari L. Cancer cell genetics shaping of the tumor microenvironment reveals myeloid cell-centric exploitable vulnerabilities in hepatocellular carcinoma. Nat Commun 2024; 15:2581. [PMID: 38519484 PMCID: PMC10959959 DOI: 10.1038/s41467-024-46835-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 03/12/2024] [Indexed: 03/25/2024] Open
Abstract
Myeloid cells are abundant and plastic immune cell subsets in the liver, to which pro-tumorigenic, inflammatory and immunosuppressive roles have been assigned in the course of tumorigenesis. Yet several aspects underlying their dynamic alterations in hepatocellular carcinoma (HCC) progression remain elusive, including the impact of distinct genetic mutations in shaping a cancer-permissive tumor microenvironment (TME). Here, in newly generated, clinically-relevant somatic female HCC mouse models, we identify cancer genetics' specific and stage-dependent alterations of the liver TME associated with distinct histopathological and malignant HCC features. Mitogen-activated protein kinase (MAPK)-activated, NrasG12D-driven tumors exhibit a mixed phenotype of prominent inflammation and immunosuppression in a T cell-excluded TME. Mechanistically, we report a NrasG12D cancer cell-driven, MEK-ERK1/2-SP1-dependent GM-CSF secretion enabling the accumulation of immunosuppressive and proinflammatory monocyte-derived Ly6Clow cells. GM-CSF blockade curbs the accumulation of these cells, reduces inflammation, induces cancer cell death and prolongs animal survival. Furthermore, GM-CSF neutralization synergizes with a vascular endothelial growth factor (VEGF) inhibitor to restrain HCC outgrowth. These findings underscore the profound alterations of the myeloid TME consequential to MAPK pathway activation intensity and the potential of GM-CSF inhibition as a myeloid-centric therapy tailored to subsets of HCC patients.
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Affiliation(s)
- Christel F A Ramirez
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Daniel Taranto
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Masami Ando-Kuri
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Marnix H P de Groot
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Efi Tsouri
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Zhijie Huang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Daniel de Groot
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Roelof J C Kluin
- Genomics Core facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Daan J Kloosterman
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Joanne Verheij
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Jing Xu
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Serena Vegna
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
- Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
| | - Leila Akkari
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
- Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
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Yang X, Yang C, Zhang S, Geng H, Zhu AX, Bernards R, Qin W, Fan J, Wang C, Gao Q. Precision treatment in advanced hepatocellular carcinoma. Cancer Cell 2024; 42:180-197. [PMID: 38350421 DOI: 10.1016/j.ccell.2024.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 12/01/2023] [Accepted: 01/17/2024] [Indexed: 02/15/2024]
Abstract
The past decade has witnessed significant advances in the systemic treatment of advanced hepatocellular carcinoma (HCC). Nevertheless, the newly developed treatment strategies have not achieved universal success and HCC patients frequently exhibit therapeutic resistance to these therapies. Precision treatment represents a paradigm shift in cancer treatment in recent years. This approach utilizes the unique molecular characteristics of individual patient to personalize treatment modalities, aiming to maximize therapeutic efficacy while minimizing side effects. Although precision treatment has shown significant success in multiple cancer types, its application in HCC remains in its infancy. In this review, we discuss key aspects of precision treatment in HCC, including therapeutic biomarkers, molecular classifications, and the heterogeneity of the tumor microenvironment. We also propose future directions, ranging from revolutionizing current treatment methodologies to personalizing therapy through functional assays, which will accelerate the next phase of advancements in this area.
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Affiliation(s)
- Xupeng Yang
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Chen Yang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Immune Regulation in Cancer Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Shu Zhang
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Haigang Geng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Andrew X Zhu
- I-Mab Biopharma, Shanghai, China; Jiahui International Cancer Center, Jiahui Health, Shanghai, China
| | - René Bernards
- Division of Molecular Carcinogenesis, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Cun Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
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42
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Li B, Li Y, Zhou H, Xu Y, Cao Y, Cheng C, Peng J, Li H, Zhang L, Su K, Xu Z, Hu Y, Lu J, Lu Y, Qian L, Wang Y, Zhang Y, Liu Q, Xie Y, Guo S, Mehal WZ, Yu D. Multiomics identifies metabolic subtypes based on fatty acid degradation allocating personalized treatment in hepatocellular carcinoma. Hepatology 2024; 79:289-306. [PMID: 37540187 PMCID: PMC10789383 DOI: 10.1097/hep.0000000000000553] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 06/26/2023] [Indexed: 08/05/2023]
Abstract
BACKGROUND AND AIMS Molecular classification is a promising tool for prognosis prediction and optimizing precision therapy for HCC. Here, we aimed to develop a molecular classification of HCC based on the fatty acid degradation (FAD) pathway, fully characterize it, and evaluate its ability in guiding personalized therapy. APPROACH AND RESULTS We performed RNA sequencing (RNA-seq), PCR-array, lipidomics, metabolomics, and proteomics analysis of 41 patients with HCC, in which 17 patients received anti-programmed cell death-1 (PD-1) therapy. Single-cell RNA sequencing (scRNA-seq) was performed to explore the tumor microenvironment. Nearly, 60 publicly available multiomics data sets were analyzed. The associations between FAD subtypes and response to sorafenib, transarterial chemoembolization (TACE), immune checkpoint inhibitor (ICI) were assessed in patient cohorts, patient-derived xenograft (PDX), and spontaneous mouse model ls. A novel molecular classification named F subtype (F1, F2, and F3) was identified based on the FAD pathway, distinguished by clinical, mutational, epigenetic, metabolic, and immunological characteristics. F1 subtypes exhibited high infiltration with immunosuppressive microenvironment. Subtype-specific therapeutic strategies were identified, in which F1 subtypes with the lowest FAD activities represent responders to compounds YM-155 and Alisertib, sorafenib, anti-PD1, anti-PD-L1, and atezolizumab plus bevacizumab (T + A) treatment, while F3 subtypes with the highest FAD activities are responders to TACE. F2 subtypes, the intermediate status between F1 and F3, are potential responders to T + A combinations. We provide preliminary evidence that the FAD subtypes can be diagnosed based on liquid biopsies. CONCLUSIONS We identified 3 FAD subtypes with unique clinical and biological characteristics, which could optimize individual cancer patient therapy and help clinical decision-making.
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Affiliation(s)
- Binghua Li
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Yunzheng Li
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Huajun Zhou
- Department of Data Science & Bioinformatics, Crown Bioscience Inc., Suzhou, Jiangsu, China
| | - Yanchao Xu
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, China
| | - Yajuan Cao
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Chunxiao Cheng
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jin Peng
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Huan Li
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Laizhu Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Ke Su
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Zhu Xu
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yue Hu
- Biobank of Nanjing Drum Tower Hospital, Department of Pathology, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Nanjing, China
| | - Jiaming Lu
- Department of Radiology, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yijun Lu
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Liyuan Qian
- Department of Hepatobiliary and Pancreatic Surgery, The First People’s Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Ye Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yuchen Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Qi Liu
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yuanyuan Xie
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Sheng Guo
- Department of Data Science & Bioinformatics, Crown Bioscience Inc., Suzhou, Jiangsu, China
| | - Wajahat Z. Mehal
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Decai Yu
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, China
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University of Chinese Medicine, Nanjing, China
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Soliman N, Saharia A, Abdelrahim M, Connor AA. Molecular profiling in the management of hepatocellular carcinoma. Curr Opin Organ Transplant 2024; 29:10-22. [PMID: 38038621 DOI: 10.1097/mot.0000000000001124] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2023]
Abstract
PURPOSE OF REVIEW The purpose of this review is to both summarize the current knowledge of hepatocellular carcinoma molecular biology and to suggest a framework in which to prospectively translate this knowledge into patient care. This is timely as recent guidelines recommend increased use of these technologies to advance personalized liver cancer care. RECENT FINDINGS The main themes covered here address germline and somatic genetic alterations recently discovered in hepatocellular carcinoma, largely owing to next generation sequencing technologies, and nascent efforts to translate these into contemporary practice. SUMMARY Early efforts of translating molecular profiling to hepatocellular carcinoma care demonstrate a growing number of potentially actionable alterations. Still lacking are a consensus on what biomarkers and technologies to adopt, at what scale and cost, and how to integrate them most effectively into care.
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Papadakos SP, Arvanitakis K, Stergiou IE, Koutsompina ML, Germanidis G, Theocharis S. γδ T Cells: A Game Changer in the Future of Hepatocellular Carcinoma Immunotherapy. Int J Mol Sci 2024; 25:1381. [PMID: 38338658 PMCID: PMC10855397 DOI: 10.3390/ijms25031381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/18/2024] [Accepted: 01/19/2024] [Indexed: 02/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) remains a global health challenge with limited treatment options and a poor prognosis for advanced-stage patients. Recent advancements in cancer immunotherapy have generated significant interest in exploring novel approaches to combat HCC. One such approach involves the unique and versatile subset of T cells known as γδ T cells. γδ T cells represent a distinct subset of T lymphocytes that differ from conventional αβ T cells in terms of antigen recognition and effector functions. They play a crucial role in immunosurveillance against various malignancies, including HCC. Recent studies have demonstrated that γδ T cells can directly recognize and target HCC cells, making them an attractive candidate for immunotherapy. In this article, we aimed to explore the role exerted by γδ T cells in the context of HCC. We investigate strategies designed to maximize the therapeutic effectiveness of these cells and examine the challenges and opportunities inherent in applying these research findings to clinical practice. The potential to bring about a revolutionary shift in HCC immunotherapy by capitalizing on the unique attributes of γδ T cells offers considerable promise for enhancing patient outcomes, warranting further investigation.
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Affiliation(s)
- Stavros P. Papadakos
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Konstantinos Arvanitakis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece;
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Ioanna E. Stergiou
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.E.S.)
| | - Maria-Loukia Koutsompina
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.E.S.)
| | - Georgios Germanidis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece;
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Stamatios Theocharis
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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Zhu Y, Wang Q, Xie X, Ma C, Qiao Y, Zhang Y, Wu Y, Gao Y, Jiang J, Liu X, Chen J, Li C, Ge G. ZBTB7B is a permissive regulator of hepatocellular carcinoma initiation by repressing c-Jun expression and function. Cell Death Dis 2024; 15:55. [PMID: 38225233 PMCID: PMC10789742 DOI: 10.1038/s41419-024-06441-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 01/02/2024] [Accepted: 01/05/2024] [Indexed: 01/17/2024]
Abstract
Hepatocarcinogenesis is a multi-step process. However, the regulators of hepatocellular carcinoma (HCC) initiation are understudied. Adult liver-specific gene expression was globally downregulated in HCC. We hypothesize that adult liver-specific genes, especially adult liver-enriched transcription factors may exert tumor-suppressive functions in HCC. In this study, we identify ZBTB7B, an adult liver-enriched transcription factor as a permissive regulator of HCC initiation. ZBTB7B is highly expressed in hepatocytes in adult livers, compared to fetal livers. To evaluate the functions of ZBTB7B in hepatocarcinogenesis, we performed hepatocyte-specific ZBTB7B knockout in hydrodynamic oncogene transfer-induced mouse liver cancer models. Hepatocyte-specific knockout of ZBTB7B promotes activated Akt and N-Ras-induced HCC development. Moreover, ZBTB7B deficiency sensitizes hepatocytes to a single oncogene Akt-induced oncogenic transformation and HCC initiation, which is otherwise incompetent in inducing HCC. ZBTB7B deficiency accelerates HCC initiation by down-regulating adult liver-specific gene expression and priming livers to a fetal-like state. The molecular mechanism underlying ZBTB7B functions in hepatocytes was investigated by integrated transcriptomic, phosphoproteomic, and chromatin immunoprecipitation-sequencing analyses. Integrative multi-omics analyses identify c-Jun as the core signaling node in ZBTB7B-deficient liver cancer initiation. c-Jun is a direct target of ZBTB7B essential to accelerated liver cancer initiation in ZBTB7B-deficient livers. Knockdown of c-Jun expression or dominant negative c-Jun expression delays HCC development in ZBTB7B-deficient livers. In addition, ZBTB7B competes with c-Jun for chromatin binding. Ectopic ZBTB7B expression attenuates the tumor-promoting functions of c-Jun. Expression of ZBTB7B signature, composed of 140 genes co-regulated by ZBTB7B and c-Jun, is significantly downregulated in early-stage HCCs compared to adjacent normal tissues, correlates to liver-specific gene expression, and is associated with good prognosis in human HCC. Thus, ZBTB7B functions as a permissive regulator of HCC initiation by directly regulating c-Jun expression and function.
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Affiliation(s)
- Yue Zhu
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Qinqin Wang
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xinyu Xie
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Cuihong Ma
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yuemei Qiao
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yu Zhang
- State Key Laboratory of Molecular Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yanjun Wu
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yuan Gao
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Jing Jiang
- Genome Tagging Project (GTP) Center, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Xin Liu
- State Key Laboratory of Molecular Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Jianfeng Chen
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
| | - Chen Li
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Gaoxiang Ge
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
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Qu Y, Gong X, Zhao Z, Zhang Z, Zhang Q, Huang Y, Xie Q, Liu Y, Wei J, Du H. Establishment and Validation of Novel Prognostic Subtypes in Hepatocellular Carcinoma Based on Bile Acid Metabolism Gene Signatures Using Bulk and Single-Cell RNA-Seq Data. Int J Mol Sci 2024; 25:919. [PMID: 38255993 PMCID: PMC10815120 DOI: 10.3390/ijms25020919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/02/2024] [Accepted: 01/03/2024] [Indexed: 01/24/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly detrimental cancer type and has limited therapeutic options, posing significant threats to human health. The development of HCC has been associated with a disorder in bile acid (BA) metabolism. In this study, we employed an integrative approach, combining various datasets and omics analyses, to comprehensively characterize the tumor microenvironment in HCC based on genes related to BA metabolism. Our analysis resulted in the classification of HCC samples into four subtypes (C1, C2a, C2b, and C3). Notably, subtype C2a, characterized by the highest bile acid metabolism score (BAMS), exhibited the highest survival probability. This subtype also demonstrated increased immune cell infiltration, lower cell cycle scores, reduced AFP levels, and a lower risk of metastasis compared to subtypes C1 and C3. Subtype C1 displayed poorer survival probability and elevated cell cycle scores. Importantly, the identified subtypes based on BAMS showed potential relevance to the gene expression of drug targets in currently approved drugs and those under clinical research. Genes encoding VEGFR (FLT4 and KDR) and MET were elevated in C2, while genes such as TGFBR1, TGFB1, ADORA3, SRC, BRAF, RET, FLT3, KIT, PDGFRA, and PDGFRB were elevated in C1. Additionally, FGFR2 and FGFR3, along with immune target genes including PDCD1 and CTLA4, were higher in C3. This suggests that subtypes C1, C2, and C3 might represent distinct potential candidates for TGFB1 inhibitors, VEGFR inhibitors, and immune checkpoint blockade treatments, respectively. Significantly, both bulk and single-cell transcriptome analyses unveiled a negative correlation between BA metabolism and cell cycle-related pathways. In vitro experiments further confirmed that the treatment of HCC cell lines with BA receptor agonist ursodeoxycholic acid led to the downregulation of the expression of cell cycle-related genes. Our findings suggest a plausible involvement of BA metabolism in liver carcinogenesis, potentially mediated through the regulation of tumor cell cycles and the immune microenvironment. This preliminary understanding lays the groundwork for future investigations to validate and elucidate the specific mechanisms underlying this potential association. Furthermore, this study provides a novel foundation for future precise molecular typing and the design of systemic clinical trials for HCC therapy.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Jinfen Wei
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou Higher Education Mega Centre, Panyu District, Guangzhou 510006, China; (Y.Q.); (X.G.); (Z.Z.); (Z.Z.); (Q.Z.); (Y.H.); (Q.X.); (Y.L.)
| | - Hongli Du
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou Higher Education Mega Centre, Panyu District, Guangzhou 510006, China; (Y.Q.); (X.G.); (Z.Z.); (Z.Z.); (Q.Z.); (Y.H.); (Q.X.); (Y.L.)
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Xiao M, Wang F, Chen N, Zhang H, Cao J, Yu Y, Zhao B, Ji J, Xu P, Li L, Shen L, Lin X, Feng XH. Smad4 sequestered in SFPQ condensates prevents TGF-β tumor-suppressive signaling. Dev Cell 2024; 59:48-63.e8. [PMID: 38103553 DOI: 10.1016/j.devcel.2023.11.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 09/18/2023] [Accepted: 11/17/2023] [Indexed: 12/19/2023]
Abstract
Loss of TGF-β growth-inhibitory responses is a hallmark of human cancer. However, the molecular mechanisms underlying the TGF-β resistance of cancer cells remain to be fully elucidated. Splicing factor proline- and glutamine-rich (SFPQ) is a prion-like RNA-binding protein that is frequently upregulated in human cancers. In this study, we identified SFPQ as a potent suppressor of TGF-β signaling. The ability of SFPQ to suppress TGF-β responses depends on its prion-like domain (PrLD) that drives liquid-liquid phase separation (LLPS). Mechanistically, SFPQ physically restrained Smad4 in its condensates, which excluded Smad4 from the Smad complex and chromatin occupancy and thus functionally dampened Smad-dependent transcriptional responses. Accordingly, SFPQ deficiency or loss of phase separation activities rendered human cells hypersensitive to TGF-β responses. Together, our data identify an important function of SFPQ through LLPS that suppresses Smad transcriptional activation and TGF-β tumor-suppressive activity.
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Affiliation(s)
- Mu Xiao
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China; Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang 321000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China.
| | - Fei Wang
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China; Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang 321000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Nuo Chen
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China; Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang 321000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Hanchenxi Zhang
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China; Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang 321000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Jin Cao
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China; Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang 321000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Yi Yu
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China; Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang 321000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Bin Zhao
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China; Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang 321000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Junfang Ji
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China; Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang 321000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Pinglong Xu
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Lei Li
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China; Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang 321000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Li Shen
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Xia Lin
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Xin-Hua Feng
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China; Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang 321000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China; The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang 310009, China.
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Diao L, He M, Xu B, Chen L, Wang Z, Yang Y, Xia S, Hu S, Guo S, Li D. Identification of Proteome-Based Immune Subtypes of Early Hepatocellular Carcinoma and Analysis of Potential Metabolic Drivers. Mol Cell Proteomics 2024; 23:100686. [PMID: 38008179 PMCID: PMC10772821 DOI: 10.1016/j.mcpro.2023.100686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 11/01/2023] [Accepted: 11/23/2023] [Indexed: 11/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, ranking fourth in frequency. The relationship between metabolic reprogramming and immune infiltration has been identified as having a crucial impact on HCC progression. However, a deeper understanding of the interplay between the immune system and metabolism in the HCC microenvironment is required. In this study, we used a proteomic dataset to identify three immune subtypes (IM1-IM3) in HCC, each of which has distinctive clinical, immune, and metabolic characteristics. Among these subtypes, IM3 was found to have the poorest prognosis, with the highest levels of immune infiltration and T-cell exhaustion. Furthermore, IM3 showed elevated glycolysis and reduced bile acid metabolism, which was strongly correlated with CD8 T cell exhaustion and regulatory T cell accumulation. Our study presents the proteomic immune stratification of HCC, revealing the possible link between immune cells and reprogramming of HCC glycolysis and bile acid metabolism, which may be a viable therapeutic strategy to improve HCC immunotherapy.
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Affiliation(s)
- Lihong Diao
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China; State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Mengqi He
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Binsheng Xu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China; College of Life Sciences, Shihezi University, Shihezi, Xinjiang, China
| | - Lanhui Chen
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Ze Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Yuting Yang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China; Shanghai Yang Zhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai, China
| | - Simin Xia
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Shengwei Hu
- College of Life Sciences, Shihezi University, Shihezi, Xinjiang, China.
| | - Shuzhen Guo
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
| | - Dong Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China; School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
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49
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Pourbagheri-Sigaroodi A, Fallah F, Bashash D, Karimi A. Unleashing the potential of gene signatures as prognostic and predictive tools: A step closer to personalized medicine in hepatocellular carcinoma (HCC). Cell Biochem Funct 2024; 42:e3913. [PMID: 38269520 DOI: 10.1002/cbf.3913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 12/14/2023] [Accepted: 12/17/2023] [Indexed: 01/26/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the growing malignancies globally, affecting a myriad of people and causing numerous cancer-related deaths. Despite therapeutic improvements in treatment strategies over the past decades, HCC still remains one of the leading causes of person-years of life lost. Numerous studies have been conducted to assess the characteristics of HCC with the aim of predicting its prognosis and responsiveness to treatment. However, the identified biomarkers have shown limited sensitivity, and the translation of these findings into clinical practice has faced challenges. The development of sequencing techniques has facilitated the exploration of a wide range of genes, leading to the emergence of gene signatures. Although several studies assessed differentially expressed genes in normal and HCC tissues to find the unique gene signature with prognostic value, to date, no study has reviewed the task, and to the best of our knowledge, this review represents the first comprehensive analysis of relevant studies in HCC. Most gene signatures focused on immune-related genes, while others investigated genes related to metabolism, autophagy, and apoptosis. Even though no identical gene signatures were found, NDRG1, SPP1, BIRC5, and NR0B1 were the most extensively studied genes with prognostic value. Finally, despite challenges such as the lack of consistent patterns in gene signatures, we believe that comprehensive analysis of pertinent gene signatures will bring us a step closer to personalized medicine in HCC, where treatment strategies can be tailored to individual patients based on their unique molecular profiles.
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Affiliation(s)
- Atieh Pourbagheri-Sigaroodi
- Pediatric Infections Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Fallah
- Pediatric Infections Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abdollah Karimi
- Pediatric Infections Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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50
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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-Like Lesions. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:842-946. [DOI: 10.1016/b978-0-7020-8228-3.00013-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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