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Vanan AG, Vesal S, Seraj P, Ghezel MA, Eini P, Talebileili M, Asgari Z, Tahmasebi S, Hashemi M, Taheriazam A. DCLK1 in gastrointestinal cancer: A driver of tumor progression and a promising therapeutic target. Int J Cancer 2025; 156:2068-2086. [PMID: 40056091 DOI: 10.1002/ijc.35365] [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: 10/24/2024] [Revised: 01/12/2025] [Accepted: 01/29/2025] [Indexed: 04/05/2025]
Abstract
Cancers of the gastrointestinal (GI) tract, including colorectal, pancreatic, and hepatocellular carcinomas, represent a significant global health burden due to their high incidence and mortality rates. Doublecortin-like kinase 1 (DCLK1), initially identified for its role in neurogenesis, has emerged as a crucial player in GI cancer progression. This review comprehensively examines the multifaceted roles of DCLK1 in GI cancers, focusing on its structural isoforms, functions in normal and inflammatory states, and contributions to cancer progression and metastasis. DCLK1 is overexpressed in various GI cancers and is associated with poor prognosis, enhanced tumorigenic potential, and increased metastatic capacity. The review discusses the molecular mechanisms through which DCLK1 influences cancer stem cell maintenance, epithelial-mesenchymal transition (EMT), and cell survival pathways, as well as its interactions with key signaling pathways such as Notch, WNT/β-catenin, and NF-κB. The potential of DCLK1 as a therapeutic target is also explored, highlighting preclinical and early clinical efforts to inhibit its function using small molecule inhibitors or monoclonal antibodies. Despite significant advancements, further research is needed to fully elucidate DCLK1's role in GI cancers and to develop effective therapeutic strategies targeting this protein.
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Affiliation(s)
- Ahmad Ghorbani Vanan
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soheil Vesal
- Department of Molecular Genetics, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran
| | - Parmida Seraj
- Department of Medicine, Tehran Medical Branch, Islamic Azad University, Tehran, Iran
| | | | - Pooya Eini
- Toxicological Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Talebileili
- Department of Microbiology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | - Zeynab Asgari
- Department of Immunology, School of Medicine Kerman University of Medical Sciences, Kerman, Iran
| | - Safa Tahmasebi
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Faculty of Advanced Science and Technology, Department of Genetics, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Faculty of Medicine, Department of Orthopedics, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
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2
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Valenti G, Laise P, Wu F, Takahashi R, Ruan T, Vasciaveo A, Jiang Z, Kobayashi H, Sunagawa M, Middelhoff M, Nienhüser H, Fu N, Malagola E, Companioni O, Hayakawa Y, Iuga AC, Califano A, Wang TC. Regulatory network analysis of Dclk1 gene expression reveals a tuft cell-ILC2 axis that inhibits pancreatic tumor progression. Cell Rep 2025; 44:115734. [PMID: 40408246 DOI: 10.1016/j.celrep.2025.115734] [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: 11/14/2024] [Revised: 01/21/2025] [Accepted: 05/02/2025] [Indexed: 05/25/2025] Open
Abstract
Doublecortin-like kinase 1 (Dclk1) expression identifies cells that are rare in normal pancreas but occur with an increased frequency in pancreatic neoplasia. The identity of these cells has been a matter of debate. We employed Dclk1 reporter mouse models and single-cell RNA sequencing (scRNA-seq) to define Dclk1-expressing cells. In normal pancreas, Dclk1 identifies subsets of ductal, islet, and acinar cells. In pancreatic neoplasia, Dclk1 identifies several cell populations, among which acinar-to-ductal metaplasia (ADM)-like cells and tuft-like cells are predominant. These two populations play opposing roles, with Dclk1+ ADM-like cells sustaining and Dclk1+ tuft-like cells restraining tumor progression. The generation of Dclk1+ tuft-like cells requires the transcription factor SPIB and is sustained by a paracrine loop involving type 2 innate lymphoid cells (ILC2s) and cancer-associated fibroblasts (CAFs) that provide interleukin (IL)-13 and IL-33, respectively. Dclk1+ tuft-like cells release angiotensinogen to restrain tumor progression. Overall, our study defines pancreatic Dclk1+ cells and unveils a protective tuft cell-ILC2 axis against pancreatic neoplasia.
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Affiliation(s)
- Giovanni Valenti
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA
| | - Pasquale Laise
- Department of Systems Biology, Columbia University, New York, NY, USA; DarwinHealth, Inc., New York, NY, USA
| | - Feijing Wu
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA
| | - Ryota Takahashi
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA
| | - Tuo Ruan
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA
| | | | - Zhengyu Jiang
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA
| | - Hiroki Kobayashi
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA
| | - Masaki Sunagawa
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA
| | - Moritz Middelhoff
- Klinik und Poliklinik für Innere Medizin II, Klinikum Rechts der Isar, TU Munich, Munich, Germany
| | - Henrik Nienhüser
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA
| | - Na Fu
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA
| | - Ermanno Malagola
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA
| | - Osmel Companioni
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA
| | - Yoku Hayakawa
- Graduate School of Medicine, Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Alina C Iuga
- Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
| | - Andrea Califano
- Department of Systems Biology, Columbia University, New York, NY, USA; DarwinHealth, Inc., New York, NY, USA; Chan Zuckerberg Biohub New York, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Department of Biochemistry and Molecular Biophysics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Biomedical Informatics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Timothy C Wang
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA.
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Lv M, Yang X, Xu C, Song Q, Zhao H, Sun T, Liu J, Zhang Y, Sun G, Xue Y, Zhang Z. SIRT4 Promotes Pancreatic Cancer Stemness by Enhancing Histone Lactylation and Epigenetic Reprogramming Stimulated by Calcium Signaling. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2412553. [PMID: 40298941 PMCID: PMC12120773 DOI: 10.1002/advs.202412553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 03/13/2025] [Indexed: 04/30/2025]
Abstract
Mitochondria Sirtuins including SIRT4 erase a variety of posttranslational modifications from mitochondria proteins, leading to metabolic reprogramming that acts as a tumor suppressor, oncogenic promotor, or both. However, the factors and the underlying mechanisms that stimulate and relay such a signaling cascade are poorly understood. Here, we reveal that the voltage-gated calcium channel subunit α2δ1-mediated calcium signaling can upregulate the expression of SIRT4, which is highly expressed in α2δ1-positive pancreatic tumor-initiating cells (TICs). Furthermore, SIRT4 is functionally sufficient and indispensable to promote TIC properties of pancreatic cancer cells by directly deacetylating ENO1 at K358, leading to attenuated ENO1's RNA-binding capacity, enhanced glycolytic substrate 2-PG affinity, and subsequently robust catalytic activity with boosted glycolytic ability and increased production of lactate acid. Interestingly, both SIRT4 and deacetylated mimetic of ENO1-K358 can increase the lactylation of histones at multiple sites including H3K9 and H3K18 sites, which resulted in epigenetic reprogramming to directly activate a variety of pathways that are essential for stemness. Hence, the study links α2δ1-mediated calcium signaling to SIRT4-mediated histone lactylation epigenetic reprogramming in promoting the stem cell-like properties of pancreatic cancer, which holds significant potential for the development of novel therapeutic strategies by targeting TICs of pancreatic cancer.
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Affiliation(s)
- Mengzhu Lv
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell BiologyPeking University Cancer Hospital & InstituteBeijing100142P. R. China
| | - Xiaodan Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell BiologyPeking University Cancer Hospital & InstituteBeijing100142P. R. China
| | - Congcong Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell BiologyPeking University Cancer Hospital & InstituteBeijing100142P. R. China
- State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal CancerThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan450052P. R. China
| | - Qingru Song
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell BiologyPeking University Cancer Hospital & InstituteBeijing100142P. R. China
| | - Hailian Zhao
- Key Laboratory of RNA Biology, Institute of BiophysicsChinese Academy of SciencesBeijing100101P. R. China
| | - Tianjiao Sun
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell BiologyPeking University Cancer Hospital & InstituteBeijing100142P. R. China
| | - Jingtao Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of PharmacyPeking University Cancer Hospital and InstituteBeijing100142P. R. China
| | - Yuan Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell BiologyPeking University Cancer Hospital & InstituteBeijing100142P. R. China
| | - Guogui Sun
- Department of ChemoradiationAffiliated Hospital of North China University of Science and TechnologyTangshanHebei063000P.R. China
| | - Yuanchao Xue
- Key Laboratory of RNA Biology, Institute of BiophysicsChinese Academy of SciencesBeijing100101P. R. China
| | - Zhiqian Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell BiologyPeking University Cancer Hospital & InstituteBeijing100142P. R. China
- State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal CancerThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan450052P. R. China
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4
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Salas-Escabillas DJ, Hoffman MT, Brender SM, Moore JS, Wen HJ, Benitz S, Davis ET, Long D, Wombwell AM, Chianis ERD, Allen-Petersen BL, Steele NG, Sears RC, Matsumoto I, DelGiorno KE, Crawford HC. Tuft cells transdifferentiate to neural-like progenitor cells in the progression of pancreatic cancer. Dev Cell 2025; 60:837-852.e3. [PMID: 39721583 DOI: 10.1016/j.devcel.2024.12.003] [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: 04/19/2024] [Revised: 09/13/2024] [Accepted: 12/02/2024] [Indexed: 12/28/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDA) is partly initiated through the transdifferentiation of acinar cells to metaplasia, which progresses to neoplasia and cancer. Tuft cells (TCs) are chemosensory cells not found in the normal pancreas but arise in cancer precursor lesions and diminish during progression to carcinoma. These metaplastic TCs (mTCs) suppress tumor progression through communication with the tumor microenvironment, but their fate during progression is unknown. To determine the fate of mTCs during PDA progression, we created a dual recombinase lineage trace model, wherein a pancreas-specific FlpO was used to induce tumorigenesis, while a tuft-cell specific Pou2f3CreERT/+ driver was used to induce expression of a tdTomato reporter. We found that mTCs in carcinoma transdifferentiate into neural-like progenitor cells (NRPs), a cell type associated with poor survival in patients. Using conditional knockout and overexpression systems, we found that Myc activity in mTCs is necessary and sufficient to induce this tuft-to-neuroendocrine transition (TNT).
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Affiliation(s)
- Daniel J Salas-Escabillas
- Cancer Biology, University of Michigan, Ann Arbor, MI, USA; Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA
| | - Megan T Hoffman
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Sydney M Brender
- Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA
| | - Jacee S Moore
- Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA
| | - Hui-Ju Wen
- Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA
| | - Simone Benitz
- Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA
| | - Erick T Davis
- Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA
| | - Daniel Long
- Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA
| | - Allison M Wombwell
- Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA
| | - Ella Rose D Chianis
- Department of Biological Sciences, Purdue University, West Lafayette, IN, USA
| | | | - Nina G Steele
- Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA
| | - Rosalie C Sears
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA
| | | | - Kathleen E DelGiorno
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Howard C Crawford
- Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA.
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5
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Pian LL, Song MH, Wang TF, Qi L, Peng TL, Xie KP. Identification and analysis of pancreatic intraepithelial neoplasia: opportunities and challenges. Front Endocrinol (Lausanne) 2025; 15:1401829. [PMID: 39839479 PMCID: PMC11746065 DOI: 10.3389/fendo.2024.1401829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 12/17/2024] [Indexed: 01/23/2025] Open
Abstract
Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion of pancreatic ductal adenocarcinoma (PDAC), which has poor prognosis with a short median overall survival of 6-12 months and a low 5-year survival rate of approximately 3%. It is crucial to remove PanIN lesions to prevent the development of invasive PDAC, as PDAC spreads rapidly outside the pancreas. This review aims to provide the latest knowledge on PanIN risk, pathology, cellular origin, genetic susceptibility, and diagnosis, while identifying research gaps that require further investigation in this understudied area of precancerous lesions. PanINs are classified into PanIN 1, PanIN 2, and PanIN 3, with PanIN 3 having the highest likelihood of developing into invasive PDAC. Differentiating between PanIN 2 and PanIN 3 is clinically significant. Genetic alterations found in PDAC are also present in PanIN and increase with the grade of PanIN. Imaging methods alone are insufficient for distinguishing PanIN, necessitating the use of genetic and molecular tests for identification. In addition, metabolomics technologies and miRNAs are playing an increasingly important role in the field of cancer diagnosis, offering more possibilities for efficient identification of PanIN. Although detecting and stratifying the risk of PanIN poses challenges, the combined utilization of imaging, genetics, and metabolomics holds promise for improving patient survival in this field.
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Affiliation(s)
- Ling-ling Pian
- School of Medicine, The South China University of Technology, Guangzhou, Guangdong, China
- Division of Gastroenterology, Institute of Digestive Disease, Affiliated Qingyuan Hospital, The Sixth Clinical Medical School, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong, China
| | - Mei-hui Song
- Division of Gastroenterology, Institute of Digestive Disease, Affiliated Qingyuan Hospital, The Sixth Clinical Medical School, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong, China
| | - Teng-fei Wang
- Division of Gastroenterology, Institute of Digestive Disease, Affiliated Qingyuan Hospital, The Sixth Clinical Medical School, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong, China
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China
| | - Ling Qi
- Division of Gastroenterology, Institute of Digestive Disease, Affiliated Qingyuan Hospital, The Sixth Clinical Medical School, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong, China
| | - Tie-li Peng
- Division of Gastroenterology, Institute of Digestive Disease, Affiliated Qingyuan Hospital, The Sixth Clinical Medical School, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong, China
| | - Ke-ping Xie
- School of Medicine, The South China University of Technology, Guangzhou, Guangdong, China
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Valenti G, Laise P, Takahashi R, Wu F, Ruan T, Vasciaveo A, Jiang Z, Sunagawa M, Middelhoff M, Nienhüser H, Fu N, Malagola E, Hayakawa Y, Iuga AC, Califano A, Wang TC. Regulatory network analysis of Dclk1 gene expression reveals a tuft cell-ILC2 axis that inhibits pancreatic tumor progression. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.30.610508. [PMID: 39257805 PMCID: PMC11383664 DOI: 10.1101/2024.08.30.610508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 09/12/2024]
Abstract
Dclk1 expression defines a rare population of cells in the normal pancreas whose frequency is increased at early stages of pancreatic tumorigenesis. The identity and the precise roles of Dclk1 expressing cells in pancreas have been matter of debate, although evidence suggests their involvement in a number of key functions, including regeneration and neoplasia. We employed a recently developed Dclk1 reporter mouse model and single cell RNAseq analysis to define Dclk1 expressing cells in normal pancreas and pancreatic neoplasia. In normal pancreas, Dclk1 epithelial expression identifies subsets of ductal, islet and acinar cells. In pancreatic neoplasia, Dclk1 expression identifies five epithelial cell populations, among which acinar-to-ductal metaplasia (ADM)-like cells and tuft-like cells are predominant. These two cell populations play opposing roles in pancreatic neoplasia, with Dclk1+ ADM-like cells sustaining tumor growth while Dclk1+ tuft-like cells restraining tumor progression. The differentiation of Kras mutant acinar cells into Dclk1+ tuft-like cells requires the activation of the transcription factor SPIB and is further supported by a cellular paracrine loop involving cancer group 2 innate lymphoid cells (ILC2) and cancer activated fibroblasts (CAFs) that provide IL13 and IL33, respectively. In turn, Dclk1+ tuft-like cells release angiotensinogen that plays protective roles against pancreatic neoplasia. Overall, our study provides novel insights on the biology of Dclk1+ cells in normal pancreas and unveils a protective axis against pancreatic neoplasia, involving CAFs, ILC2 and Dclk1+ tuft-like cells, which ultimately results in angiotensinogen release.
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Affiliation(s)
- Giovanni Valenti
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York, USA
- These authors contributed equally
| | - Pasquale Laise
- Department of Systems Biology, Columbia University, New York, New York, USA
- DarwinHealth Inc., New York, New York, USA
- These authors contributed equally
| | - Ryota Takahashi
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York, USA
| | - Feijing Wu
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York, USA
| | - Tuo Ruan
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York, USA
| | | | - Zhengyu Jiang
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York, USA
| | - Masaki Sunagawa
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York, USA
| | - Moritz Middelhoff
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, TU Munich, Germany
| | - Henrik Nienhüser
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York, USA
| | - Na Fu
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York, USA
| | - Ermanno Malagola
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York, USA
| | - Yoku Hayakawa
- Graduate School of Medicine, Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Alina C. Iuga
- Department of Pathology and Cell Biology, Columbia University, New York, New York, USA
| | - Andrea Califano
- Department of Systems Biology, Columbia University, New York, New York, USA
| | - Timothy C. Wang
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York, USA
- Lead Contact
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Li M, Zuo J, Yang K, Wang P, Zhou S. Proteomics mining of cancer hallmarks on a single-cell resolution. MASS SPECTROMETRY REVIEWS 2024; 43:1019-1040. [PMID: 37051664 DOI: 10.1002/mas.21842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 11/25/2022] [Accepted: 03/15/2023] [Indexed: 06/19/2023]
Abstract
Dysregulated proteome is an essential contributor in carcinogenesis. Protein fluctuations fuel the progression of malignant transformation, such as uncontrolled proliferation, metastasis, and chemo/radiotherapy resistance, which severely impair therapeutic effectiveness and cause disease recurrence and eventually mortality among cancer patients. Cellular heterogeneity is widely observed in cancer and numerous cell subtypes have been characterized that greatly influence cancer progression. Population-averaged research may not fully reveal the heterogeneity, leading to inaccurate conclusions. Thus, deep mining of the multiplex proteome at the single-cell resolution will provide new insights into cancer biology, to develop prognostic biomarkers and treatments. Considering the recent advances in single-cell proteomics, herein we review several novel technologies with particular focus on single-cell mass spectrometry analysis, and summarize their advantages and practical applications in the diagnosis and treatment for cancer. Technological development in single-cell proteomics will bring a paradigm shift in cancer detection, intervention, and therapy.
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Affiliation(s)
- Maomao Li
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China
| | - Jing Zuo
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China
| | - Kailin Yang
- Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, Ohio, USA
| | - Ping Wang
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China
| | - Shengtao Zhou
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China
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8
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Baldan J, Camacho-Roda J, Ballester M, Høj K, Kurilla A, Maurer HC, Arcila-Barrera S, Lin X, Pan Z, Castro JL, Mayorca-Guiliani AE, Rift CV, Hasselby J, Bouwens L, Lefebvre V, David CJ, Parnas O, DelGiorno KE, Erler JT, Rooman I, Arnes L. Resolution of Acinar Dedifferentiation Regulates Tissue Remodeling in Pancreatic Injury and Cancer Initiation. Gastroenterology 2024; 167:718-732.e18. [PMID: 38729450 DOI: 10.1053/j.gastro.2024.04.031] [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: 06/26/2023] [Revised: 04/02/2024] [Accepted: 04/29/2024] [Indexed: 05/12/2024]
Abstract
BACKGROUND & AIMS Acinar-to-ductal metaplasia (ADM) is crucial in the development of pancreatic ductal adenocarcinoma. However, our understanding of the induction and resolution of ADM remains limited. We conducted comparative transcriptome analyses to identify conserved mechanisms of ADM in mouse and human. METHODS We identified Sox4 among the top up-regulated genes. We validated the analysis by RNA in situ hybridization. We performed experiments in mice with acinar-specific deletion of Sox4 (Ptf1a: CreER; Rosa26-LSL-YFPLSL-YFP; Sox4fl/fl) with and without an activating mutation in Kras (KrasLSL-G12D/+). Mice were given caerulein to induce pancreatitis. We performed phenotypic analysis by immunohistochemistry, tissue decellularization, and single-cell RNA sequencing. RESULTS We demonstrated that Sox4 is reactivated in ADM and pancreatic intraepithelial neoplasias. Contrary to findings in other tissues, Sox4 actually counteracts cellular dedifferentiation and helps maintain tissue homeostasis. Moreover, our investigations unveiled the indispensable role of Sox4 in the specification of mucin-producing cells and tuft-like cells from acinar cells. We identified Sox4-dependent non-cell-autonomous mechanisms regulating the stromal reaction during disease progression. Notably, Sox4-inferred targets are activated upon KRAS inactivation and tumor regression. CONCLUSIONS Our results indicate that our transcriptome analysis can be used to investigate conserved mechanisms of tissue injury. We demonstrate that Sox4 restrains acinar dedifferentiation and is necessary for the specification of acinar-derived metaplastic cells in pancreatic injury and cancer initiation and is activated upon Kras ablation and tumor regression in mice. By uncovering novel potential strategies to promote tissue homeostasis, our findings offer new avenues for preventing the development of pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Jonathan Baldan
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark; Translational Oncology Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
| | - Juan Camacho-Roda
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Marta Ballester
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Kristina Høj
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Anita Kurilla
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - H Carlo Maurer
- Department of Internal Medicine II, Technical University of Munich, Munich, Germany
| | - Sebastian Arcila-Barrera
- The Lautenberg Center for Immunology and Cancer Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Xinyi Lin
- Tsinghua University School of Medicine, Beijing, China; Peking University-Tsinghua Center for Life Sciences, Beijing, China
| | - Zhaolong Pan
- Translational Oncology Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - Joana Leitão Castro
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | | | - Charlotte Vestrup Rift
- Department of Pathology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Jane Hasselby
- Department of Pathology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Luc Bouwens
- Cell Differentiation Lab, Vrije Universiteit Brussel, Brussels, Belgium
| | - Véronique Lefebvre
- Department of Surgery/Division of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Charles J David
- Tsinghua University School of Medicine, Beijing, China; Peking University-Tsinghua Center for Life Sciences, Beijing, China
| | - Oren Parnas
- The Lautenberg Center for Immunology and Cancer Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | | | - Janine Terra Erler
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Ilse Rooman
- Translational Oncology Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - Luis Arnes
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
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9
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Storz P. Earliest Metabolic Changes Associated with the Initiation of Pancreatic Cancer. Cancer Res 2024; 84:2225-2226. [PMID: 39005051 DOI: 10.1158/0008-5472.can-24-0874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 04/22/2024] [Indexed: 07/16/2024]
Abstract
Pancreatic cancer is usually detected at a late stage, when tumors have already metastasized; therefore, it has a poor prognosis with a 5-year survival rate of 11% to 12%. A key to targeting this high mortality is to develop methods for detecting the disease at a stage in which it is still local to the pancreas. However, this needs a better understanding of the events that govern pancreatic cancer oncogenesis. In this issue of Cancer Research, Neuß and colleagues report metabolic changes associated with acinar-to-ductal metaplasia (ADM), an initiating event that leads to the formation of precursor lesions for pancreatic ductal adenocarcinoma (PDAC). Their findings reveal a switch to aerobic glycolysis, increased c-MYC signaling, and increased serine metabolism as driving factors for the ADM process. These findings are important as they demonstrate that metabolic changes that drive the proliferation and metastasis of full-blown PDAC begin in the earliest lesions. The data not only provide insights into how PDAC develops but also a potential explanation for previously described findings, such as circulating lesion cells can be detected even when no carcinoma in situ is present. In summary, this article is highly relevant for furthering our understanding of how metabolic reprogramming drives the earliest events leading to PDAC development and could lay the groundwork for developing methods for early detection or intervention. See related article by Neuß et al., p. 2297.
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Affiliation(s)
- Peter Storz
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida
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10
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Saleh O, Shihadeh H, Yousef A, Erekat H, Abdallh F, Al-Leimon A, Elsalhy R, Altiti A, Dajani M, AlBarakat MM. The Effect of Intratumor Heterogeneity in Pancreatic Ductal Adenocarcinoma Progression and Treatment. Pancreas 2024; 53:e450-e465. [PMID: 38728212 DOI: 10.1097/mpa.0000000000002342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/12/2024]
Abstract
BACKGROUND AND OBJECTIVES Pancreatic cancer is one of the most lethal malignancies. Even though many substantial improvements in the survival rates for other major cancer forms were made, pancreatic cancer survival rates have remained relatively unchanged since the 1960s. Even more, no standard classification system for pancreatic cancer is based on cellular biomarkers. This review will discuss and provide updates about the role of stem cells in the progression of PC, the genetic changes associated with it, and the promising biomarkers for diagnosis. MATERIALS AND METHODS The search process used PubMed, Cochrane Library, and Scopus databases to identify the relevant and related articles. Articles had to be published in English to be considered. RESULTS The increasing number of studies in recent years has revealed that the diversity of cancer-associated fibroblasts is far greater than previously acknowledged, which highlights the need for further research to better understand the various cancer-associated fibroblast subpopulations. Despite the huge diversity in pancreatic cancer, some common features can be noted to be shared among patients. Mutations involving CDKN2, P53, and K-RAS can be seen in a big number of patients, for example. Similarly, some patterns of genes and biomarkers expression and the level of their expression can help in predicting cancer behavior such as metastasis and drug resistance. The current trend in cancer research, especially with the advancement in technology, is to sequence everything in hopes of finding disease-related mutations. CONCLUSION Optimizing pancreatic cancer treatment requires clear classification, understanding CAF roles, and exploring stroma reshaping approaches.
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Affiliation(s)
- Othman Saleh
- From the Faculty of Medicine, The Hashemite University, Zarqa
| | | | | | - Hana Erekat
- School of medicine, University of Jordan, Amman
| | - Fatima Abdallh
- From the Faculty of Medicine, The Hashemite University, Zarqa
| | | | | | | | - Majd Dajani
- From the Faculty of Medicine, The Hashemite University, Zarqa
| | - Majd M AlBarakat
- Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
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11
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Salas-Escabillas DJ, Hoffman MT, Moore JS, Brender SM, Wen HJ, Benitz S, Davis ET, Long D, Wombwell AM, Steele NG, Sears RC, Matsumoto I, DelGiorno KE, Crawford HC. Tuft cells transdifferentiate to neural-like progenitor cells in the progression of pancreatic cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.12.579982. [PMID: 38405804 PMCID: PMC10888969 DOI: 10.1101/2024.02.12.579982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/27/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDA) is partly initiated through the transdifferentiation of acinar cells to metaplastic ducts that act as precursors of neoplasia and cancer. Tuft cells are solitary chemosensory cells not found in the normal pancreas but arise in metaplasia and neoplasia, diminishing as neoplastic lesions progress to carcinoma. Metaplastic tuft cells (mTCs) function to suppress tumor progression through communication with the tumor microenvironment, but their fate during progression is unknown. To determine the fate of mTCs during PDA progression, we have created a lineage tracing model that uses a tamoxifen-inducible tuft-cell specific Pou2f3CreERT/+ driver to induce transgene expression, including the lineage tracer tdTomato or the oncogene Myc. mTC lineage trace models of pancreatic neoplasia and carcinoma were used to follow mTC fate. We found that mTCs, in the carcinoma model, transdifferentiate into neural-like progenitor cells (NRPs), a cell type associated with poor survival in PDA patients. Using conditional knock-out and overexpression systems, we found that Myc activity in mTCs is necessary and sufficient to induce this Tuft-to-Neuroendocrine-Transition (TNT).
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Affiliation(s)
- Daniel J. Salas-Escabillas
- Cancer Biology, University of Michigan, Ann Arbor, MI
- Department of Surgery, Henry Ford Health, Detroit, MI
| | - Megan T. Hoffman
- Department of Immunology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | | | | | - Hui-Ju Wen
- Department of Surgery, Henry Ford Health, Detroit, MI
| | - Simone Benitz
- Department of Surgery, Henry Ford Health, Detroit, MI
| | | | - Dan Long
- Department of Surgery, Henry Ford Health, Detroit, MI
| | | | | | - Rosalie C. Sears
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR
| | | | - Kathleen E. DelGiorno
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN
| | - Howard C. Crawford
- Department of Surgery, Henry Ford Health, Detroit, MI
- Cancer Biology Program, Wayne State University, Detroit, MI
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12
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Di Chiaro P, Nacci L, Arco F, Brandini S, Polletti S, Palamidessi A, Donati B, Soriani C, Gualdrini F, Frigè G, Mazzarella L, Ciarrocchi A, Zerbi A, Spaggiari P, Scita G, Rodighiero S, Barozzi I, Diaferia GR, Natoli G. Mapping functional to morphological variation reveals the basis of regional extracellular matrix subversion and nerve invasion in pancreatic cancer. Cancer Cell 2024; 42:662-681.e10. [PMID: 38518775 DOI: 10.1016/j.ccell.2024.02.017] [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: 12/21/2022] [Revised: 12/07/2023] [Accepted: 02/27/2024] [Indexed: 03/24/2024]
Abstract
Intratumor morphological heterogeneity of pancreatic ductal adenocarcinoma (PDAC) predicts clinical outcomes but is only partially understood at the molecular level. To elucidate the gene expression programs underpinning intratumor morphological variation in PDAC, we investigated and deconvoluted at single cell level the molecular profiles of histologically distinct clusters of PDAC cells. We identified three major morphological and functional variants that co-exist in varying proportions in all PDACs, display limited genetic diversity, and are associated with a distinct organization of the extracellular matrix: a glandular variant with classical ductal features; a transitional variant displaying abortive ductal structures and mixed endodermal and myofibroblast-like gene expression; and a poorly differentiated variant lacking ductal features and basement membrane, and showing neuronal lineage priming. Ex vivo and in vitro evidence supports the occurrence of dynamic transitions among these variants in part influenced by extracellular matrix composition and stiffness and associated with local, specifically neural, invasion.
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Affiliation(s)
- Pierluigi Di Chiaro
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milano, Italy.
| | - Lucia Nacci
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milano, Italy
| | - Fabiana Arco
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milano, Italy
| | - Stefania Brandini
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milano, Italy
| | - Sara Polletti
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milano, Italy
| | - Andrea Palamidessi
- IFOM, The FIRC Institute for Molecular Oncology, Via Adamello 16, 20139 Milan, Italy
| | - Benedetta Donati
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Chiara Soriani
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milano, Italy
| | - Francesco Gualdrini
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milano, Italy
| | - Gianmaria Frigè
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milano, Italy
| | - Luca Mazzarella
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milano, Italy; Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, IEO, European Institute of Oncology, IRCCS, Milano, Italy
| | - Alessia Ciarrocchi
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Alessandro Zerbi
- IRCCS Humanitas Research Hospital, Rozzano, Milano, Italy; Humanitas University, Pieve Emanuele - Milano, Italy
| | | | - Giorgio Scita
- IFOM, The FIRC Institute for Molecular Oncology, Via Adamello 16, 20139 Milan, Italy; Department of Oncology and Haemato-Oncology, University of Milan, Milano, Italy
| | - Simona Rodighiero
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milano, Italy
| | - Iros Barozzi
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Giuseppe R Diaferia
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milano, Italy.
| | - Gioacchino Natoli
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milano, Italy.
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13
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Gholamzad A, Khakpour N, Khosroshahi EM, Asadi S, Koohpar ZK, Matinahmadi A, Jebali A, Rashidi M, Hashemi M, Sadi FH, Gholamzad M. Cancer stem cells: The important role of CD markers, Signaling pathways, and MicroRNAs. Pathol Res Pract 2024; 256:155227. [PMID: 38490099 DOI: 10.1016/j.prp.2024.155227] [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: 11/28/2023] [Revised: 02/23/2024] [Accepted: 02/25/2024] [Indexed: 03/17/2024]
Abstract
For the first time, a subset of small cancer cells identified in acute myeloid leukemia has been termed Cancer Stem Cells (CSCs). These cells are notorious for their robust proliferation, self-renewal abilities, significant tumor-forming potential, spread, and resistance to treatments. CSCs are a global concern, as it found in numerous types of cancer, posing a real-world challenge today. Our review encompasses research on key CSC markers, signaling pathways, and MicroRNA in three types of cancer: breast, colon, and liver. These factors play a critical role in either promoting or inhibiting cancer cell growth. The reviewed studies have shown that as cells undergo malignant transformation, there can be an increase or decrease in the expression of different Cluster of Differentiation (CD) markers on their surface. Furthermore, alterations in essential signaling pathways, such as Wnt and Notch1, may impact CSC proliferation, survival, and movement, while also providing potential targets for cancer therapies. Additionally, some research has focused on MicroRNAs due to their dual role as potential therapeutic biomarkers and their ability to enhance CSCs' response to anti-cancer drugs. MicroRNAs also regulate a wide array of cellular processes, including the self-renewal and pluripotency of CSCs, and influence gene transcription. Thus, these studies indicate that MicroRNAs play a significant role in the malignancy of various tumors. Although the gathered information suggests that specific CSC markers, signaling pathways, and MicroRNAs are influential in determining the destiny of cancer cells and could be advantageous for therapeutic strategies, their precise roles and impacts remain incompletely defined, necessitating further investigation.
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Affiliation(s)
- Amir Gholamzad
- Department of Microbiology and Immunology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Niloofar Khakpour
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Elaheh Mohandesi Khosroshahi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Saba Asadi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Zeinab Khazaei Koohpar
- Department of Cell and Molecular Biology, Faculty of Biological Sciences,Tonekabon Branch,Islamic Azad University, Tonekabon, Iran
| | - Arash Matinahmadi
- Department of Cellular and Molecular Biology, Nicolaus Copernicus,Torun,Poland
| | - Ali Jebali
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Deprtment of Medical Nanotechnology,Faculty of Advanced Sciences and Technology,Tehran Medical Sciences,Islamic Azad University, Tehran, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran.
| | | | - Mehrdad Gholamzad
- Department of Microbiology and Immunology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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14
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Middonti E, Astanina E, Vallariello E, Hoza RM, Metovic J, Spadi R, Cristiano C, Papotti M, Allavena P, Novelli F, Parab S, Cappello P, Scarpa A, Lawlor R, Di Maio M, Arese M, Bussolino F. A neuroligin-2-YAP axis regulates progression of pancreatic intraepithelial neoplasia. EMBO Rep 2024; 25:1886-1908. [PMID: 38413734 PMCID: PMC11014856 DOI: 10.1038/s44319-024-00104-x] [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: 06/05/2023] [Revised: 02/05/2024] [Accepted: 02/13/2024] [Indexed: 02/29/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a dismal prognosis that arises from precursor lesions called pancreatic intraepithelial neoplasias (PanINs). Progression from low- to high-grade PanINs is considered as tumor initiation, and a deeper understanding of this switch is needed. Here, we show that synaptic molecule neuroligin-2 (NLGN2) is expressed by pancreatic exocrine cells and plays a crucial role in the regulation of contact inhibition and epithelial polarity, which characterize the switch from low- to high-grade PanIN. NLGN2 localizes to tight junctions in acinar cells, is diffusely distributed in the cytosol in low-grade PanINs and is lost in high-grade PanINs and in a high percentage of advanced PDACs. Mechanistically, NLGN2 is necessary for the formation of the PALS1/PATJ complex, which in turn induces contact inhibition by reducing YAP function. Our results provide novel insights into NLGN2 functions outside the nervous system and can be used to model PanIN progression.
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Affiliation(s)
- Emanuele Middonti
- Department of Oncology, University of Torino, 10043, Orbassano, Italy.
- Candiolo Cancer Institute-IRCCS-FPO, 10060, Candiolo, Italy.
| | - Elena Astanina
- Department of Oncology, University of Torino, 10043, Orbassano, Italy
- Candiolo Cancer Institute-IRCCS-FPO, 10060, Candiolo, Italy
| | - Edoardo Vallariello
- Department of Oncology, University of Torino, 10043, Orbassano, Italy
- Candiolo Cancer Institute-IRCCS-FPO, 10060, Candiolo, Italy
| | - Roxana Maria Hoza
- Department of Oncology, University of Torino, 10043, Orbassano, Italy
- Candiolo Cancer Institute-IRCCS-FPO, 10060, Candiolo, Italy
| | - Jasna Metovic
- Department of Oncology, University of Torino, 10043, Orbassano, Italy
| | - Rosella Spadi
- SC Oncologia Medica, Città della Salute e della Scienza di Torino, 10126, Torino, Italy
| | - Carmen Cristiano
- SC Oncologia Medica, Città della Salute e della Scienza di Torino, 10126, Torino, Italy
| | - Mauro Papotti
- Department of Oncology, University of Torino, 10043, Orbassano, Italy
- Division of Pathology at Città della Salute e della Scienza di Torino, 10126, Torino, Italy
| | - Paola Allavena
- IRCCS, Humanitas Clinical and Research Center, 20089, Rozzano, Italy
| | - Francesco Novelli
- Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126, Torino, Italy
- Laboratory of Tumor Immunology, Center for Experimental Research and Medical Studies, Città della Salute e della Scienza di Torino, 10126, Torino, Italy
- Molecular Biotechnology Center, University of Torino, 10125, Torino, Italy
| | - Sushant Parab
- Department of Oncology, University of Torino, 10043, Orbassano, Italy
- Candiolo Cancer Institute-IRCCS-FPO, 10060, Candiolo, Italy
| | - Paola Cappello
- Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126, Torino, Italy
- Laboratory of Tumor Immunology, Center for Experimental Research and Medical Studies, Città della Salute e della Scienza di Torino, 10126, Torino, Italy
- Molecular Biotechnology Center, University of Torino, 10125, Torino, Italy
| | - Aldo Scarpa
- Applied Research Center (ARC-NET), University of Verona, 37134, Verona, Italy
- Department of Diagnostics and Public Health, University of Verona, 37134, Verona, Italy
| | - Rita Lawlor
- Applied Research Center (ARC-NET), University of Verona, 37134, Verona, Italy
- Department of Diagnostics and Public Health, University of Verona, 37134, Verona, Italy
| | - Massimo Di Maio
- Department of Oncology, University of Torino, 10043, Orbassano, Italy
- Medical Oncology, Ordine Mauriziano Hospital, 10128, Torino, Italy
| | - Marco Arese
- Department of Oncology, University of Torino, 10043, Orbassano, Italy
- Candiolo Cancer Institute-IRCCS-FPO, 10060, Candiolo, Italy
| | - Federico Bussolino
- Department of Oncology, University of Torino, 10043, Orbassano, Italy.
- Candiolo Cancer Institute-IRCCS-FPO, 10060, Candiolo, Italy.
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15
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Weng L, Zhou J, Guo S, Xu N, Ma R. The molecular subtyping and precision medicine in triple-negative breast cancer---based on Fudan TNBC classification. Cancer Cell Int 2024; 24:120. [PMID: 38555429 PMCID: PMC10981301 DOI: 10.1186/s12935-024-03261-0] [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: 09/29/2023] [Accepted: 02/02/2024] [Indexed: 04/02/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is widely recognized as the most aggressive form of breast cancer, occurring more frequently in younger patients and characterized by high heterogeneity, early distant metastases and poor prognosis. Multiple treatment options have failed to achieve the expected therapeutic effects due to the lack of clear molecular targets. Based on genomics, transcriptomics and metabolomics, the multi-omics analysis further clarifies TNBC subtyping, which provides a greater understanding of tumour heterogeneity and targeted therapy sensitivity. For instance, the luminal androgen receptor subtype (LAR) exhibits responsiveness to anti-AR therapy, and the basal-like immune-suppressed subtype (BLIS) tends to benefit from poly (ADP-ribose) polymerase inhibitors (PARPis) and anti-angiogenic therapy. The efficacy of multi-dimensional combination therapy holds immense importance in guiding personalized and precision medicine for TNBC. This review offers a systematic overview of recent FuDan TNBC molecular subtyping and its role in the instruction of clinical precision therapy.
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Affiliation(s)
- Lijuan Weng
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
- Department of Radiotherapy and Chemotherapy, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Jianliang Zhou
- Department of Radiotherapy and Chemotherapy, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Shenchao Guo
- Department of Radiotherapy and Chemotherapy, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Nong Xu
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China.
| | - Ruishuang Ma
- Department of Radiotherapy and Chemotherapy, The First Affiliated Hospital of Ningbo University, Ningbo, China.
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16
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Strine MS, Fagerberg E, Darcy PW, Barrón GM, Filler RB, Alfajaro MM, D'Angelo-Gavrish N, Wang F, Graziano VR, Menasché BL, Damo M, Wang YT, Howitt MR, Lee S, Joshi NS, Mucida D, Wilen CB. Intestinal tuft cell immune privilege enables norovirus persistence. Sci Immunol 2024; 9:eadi7038. [PMID: 38517952 PMCID: PMC11555782 DOI: 10.1126/sciimmunol.adi7038] [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: 05/12/2023] [Accepted: 02/28/2024] [Indexed: 03/24/2024]
Abstract
The persistent murine norovirus strain MNVCR6 is a model for human norovirus and enteric viral persistence. MNVCR6 causes chronic infection by directly infecting intestinal tuft cells, rare chemosensory epithelial cells. Although MNVCR6 induces functional MNV-specific CD8+ T cells, these lymphocytes fail to clear infection. To examine how tuft cells promote immune escape, we interrogated tuft cell interactions with CD8+ T cells by adoptively transferring JEDI (just EGFP death inducing) CD8+ T cells into Gfi1b-GFP tuft cell reporter mice. Unexpectedly, some intestinal tuft cells partially resisted JEDI CD8+ T cell-mediated killing-unlike Lgr5+ intestinal stem cells and extraintestinal tuft cells-despite seemingly normal antigen presentation. When targeting intestinal tuft cells, JEDI CD8+ T cells predominantly adopted a T resident memory phenotype with decreased effector and cytotoxic capacity, enabling tuft cell survival. JEDI CD8+ T cells neither cleared nor prevented MNVCR6 infection in the colon, the site of viral persistence, despite targeting a virus-independent antigen. Ultimately, we show that intestinal tuft cells are relatively resistant to CD8+ T cells independent of norovirus infection, representing an immune-privileged niche that can be leveraged by enteric microbes.
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Affiliation(s)
- Madison S Strine
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
| | - Eric Fagerberg
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
| | - Patrick W Darcy
- Laboratory of Mucosal Immunology, Rockefeller University, New York, NY, USA
| | - Gabriel M Barrón
- Program in Immunology, Stanford University, Stanford, CA, USA
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Renata B Filler
- Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Mia Madel Alfajaro
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
- Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA
| | | | - Fang Wang
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
| | - Vincent R Graziano
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT, USA
| | - Bridget L Menasché
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
- Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Martina Damo
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
| | - Ya-Ting Wang
- SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Tsinghua University School of Medicine, Beijing, China
| | - Michael R Howitt
- Program in Immunology, Stanford University, Stanford, CA, USA
- Department of Pathology, Stanford University, Stanford, CA, USA
- Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA
| | - Sanghyun Lee
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA
| | - Nikhil S Joshi
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
| | - Daniel Mucida
- Laboratory of Mucosal Immunology, Rockefeller University, New York, NY, USA
- Howard Hughes Medical Institute, Rockefeller University, New York, NY, USA
| | - Craig B Wilen
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
- Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA
- Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA
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17
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Döppler HR, Storz P. Macrophage-induced reactive oxygen species in the initiation of pancreatic cancer: a mini-review. Front Immunol 2024; 15:1278807. [PMID: 38576613 PMCID: PMC10991718 DOI: 10.3389/fimmu.2024.1278807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 03/12/2024] [Indexed: 04/06/2024] Open
Abstract
Pancreatic inflammation is a risk factor for the development of pancreatic cancer. Increased presence of inflammatory macrophages can be found in response to a KRAS mutation in acinar cells or in response to experimentally-induced pancreatitis. Inflammatory macrophages induce pancreatic acinar cells to undergo dedifferentiation to a duct-like progenitor stage, a process called acinar-to-ductal metaplasia (ADM). Occurrence of ADM lesions are believed to be the initiating event in tumorigenesis. Here we will discuss how macrophage-induced oxidative stress contributes to ADM and how ADM cells shape the fibrotic stroma needed for further progression.
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Affiliation(s)
| | - Peter Storz
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, United States
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18
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Wu X, Li S, Yang Y, Hu J, Yang T. Correlation Between DCAMKL-1 Protein Expression and K-ras Gene Mutation in Colorectal Cancer. Cancer Manag Res 2024; 16:11-21. [PMID: 38196736 PMCID: PMC10775797 DOI: 10.2147/cmar.s440845] [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: 10/10/2023] [Accepted: 12/23/2023] [Indexed: 01/11/2024] Open
Abstract
Aim To investigate the correlation between doublecortin and CaM kinase-like-1 (DCAMKL-1) protein expression, K-ras gene mutation, and their impact on patient prognosis in colorectal cancer (CRC). Methods Immunohistochemistry was used to detect the expression of DCAMKL-1 protein in 60 cases of colorectal adenoma, 82 cases of CRC (including 65 cases of lymph node metastasis) and paraffin-embedded paracancerous intestinal mucosal tissue. K-ras gene mutations in primary CRC lesions were detected using an amplification-refractory mutation system and fluorescent polymerase chain reaction. The relationship between DCAMKL-1 protein expression and K-ras gene mutations with the clinicopathological characteristics of patients with CRC was analyzed. Univariate Kaplan‒Meier survival analysis and multivariate Cox regression analysis were performed using follow-up data. Results The mutation rate of the K-ras gene in 82 cases of CRC was 48.8% (40/82). The positivity rate for the presence of DCAMKL-1 protein in CRC was 70.7% (58/82), significantly higher than that for colorectal adenomas (53.3%; 32/60) and paracancerous intestinal mucosa (0%; 0/82) (P<0.05). The positive expression rate for the presence of DCAMKL-1 protein in 65 patients with lymph node metastasis was higher in the primary lesions (69.2%; 45/65) than in the lymph node metastases (52.3%; 34/65) (χ2=12.087, P=0.001). The K-ras gene mutation status was positively correlated with DCAMKL-1 protein expression (r=0.252, P=0.022). Conclusion In this study, a potential positive correlation between K-ras gene mutation and DCAMKL-1 protein expression was identified in CRC tissues. The assessment of K-ras gene mutation status and DCAMKL-1 protein expression holds promise for augmenting early diagnosis and prognosis evaluation in CRC. This approach may improve the overall prognosis and survival outcomes for CRC patients.
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Affiliation(s)
- Xuefang Wu
- Department of Pathology, The Affiliated People’s Hospital of Ningbo University, Ningbo, 315100, People’s Republic of China
- Department of Pathology, Guizhou Provincial People’s Hospital, Guiyang, 550002, People’s Republic of China
| | - Shuang Li
- Department of Pathology, Guizhou Provincial People’s Hospital, Guiyang, 550002, People’s Republic of China
| | - Yingchun Yang
- Department of Pathology, Guizhou Provincial People’s Hospital, Guiyang, 550002, People’s Republic of China
| | - Jianjun Hu
- Department of Pathology, Guizhou Provincial People’s Hospital, Guiyang, 550002, People’s Republic of China
| | - Tongyin Yang
- Department of Pathology, Guizhou Provincial People’s Hospital, Guiyang, 550002, People’s Republic of China
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19
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Ruz-Caracuel I, Pedraza-Arevalo S, Alonso-Gordoa T, Molina-Cerrillo J, Earl J, Sainz B. Everything you ever wanted to know about cancer stem cells in neuroendocrine neoplasms but were afraid to ask. ENDOCRINE ONCOLOGY (BRISTOL, ENGLAND) 2024; 4:e240006. [PMID: 39822777 PMCID: PMC11737516 DOI: 10.1530/eo-24-0006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 08/28/2024] [Accepted: 10/30/2024] [Indexed: 01/19/2025]
Abstract
While the role of cancer stem cells (CSCs) in tumorigenesis, chemoresistance, metastasis, and relapse has been extensively studied in solid tumors, such as adenocarcinomas or sarcomas, the same cannot be said for neuroendocrine neoplasms (NENs). While lagging, CSCs have been described in numerous NENs, including gastrointestinal and pancreatic NENs (PanNENs), and they have been found to play critical roles in tumor initiation, progression, and treatment resistance. However, it seems that there is still skepticism regarding the role of CSCs in NENs, even in light of studies that support the CSC model in these tumors and the therapeutic benefits of targeting them. For example, in lung neuroendocrine carcinoids, a high percentage of CSCs have been found in atypical carcinoids, suggesting the presence of CSCs in these cancers. In PanNENs, CSCs marked by aldehyde dehydrogenases or CD90 have been identified, and targeting CSCs with inhibitors of molecular pathways has shown therapeutic potential. Overall, while evidence exists for the presence of CSCs in NENs, either the CSC field has neglected NENs or the NEN field has not fully embraced the CSC model. Both might apply and/or may be a consequence of the fact that NENs are a relatively rare and heterogeneous tumor entity, with confusing histology and nomenclature to match. Regardless, this review intends to summarize our current knowledge of CSCs in NENs and highlight the importance of understanding the role of CSCs in the biology of these rare tumors, with a special focus on developing targeted therapies to improve patients' outcomes.
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Affiliation(s)
- Ignacio Ruz-Caracuel
- Pathology Department, Hospital
Universitario Ramón y Cajal, Madrid,
Spain
- Molecular Pathology of Cancer
Group, Area 3 Cancer, Instituto Ramón y Cajal de Investigación
Sanitaria (IRYCIS), Madrid,
Spain
- Centro de Investigación
Biomédica en Red, CIBERONC, ISCIII, Madrid,
Spain
| | - Sergio Pedraza-Arevalo
- Maimonides Biomedical Research
Institute of Córdoba (IMIBIC), Cordoba,
Spain
- Department of Cell Biology,
Physiology, and Immunology, University of Córdoba,
Cordoba, Spain
- Reina Sofía University
Hospital (HURS), Cordoba,
Spain
| | - Teresa Alonso-Gordoa
- Molecular Pathology of Cancer
Group, Area 3 Cancer, Instituto Ramón y Cajal de Investigación
Sanitaria (IRYCIS), Madrid,
Spain
- Medical Oncology Department,
Hospital Universitario Ramón y Cajal, Madrid,
Spain
| | | | - Julie Earl
- Centro de Investigación
Biomédica en Red, CIBERONC, ISCIII, Madrid,
Spain
- Biomarkers and Personalized
Approach to Cancer (BIOPAC) Group, Area 3 Cancer, Instituto Ramón y Cajal
de Investigación Sanitaria (IRYCIS), Madrid,
Spain
| | - Bruno Sainz
- Centro de Investigación
Biomédica en Red, CIBERONC, ISCIII, Madrid,
Spain
- Biomarkers and Personalized
Approach to Cancer (BIOPAC) Group, Area 3 Cancer, Instituto Ramón y Cajal
de Investigación Sanitaria (IRYCIS), Madrid,
Spain
- Department of Cancer, Instituto
de Investigaciones Biomédicas (IIBm) Sols-Morreale
(CSIC-UAM), Madrid, Spain
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20
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Jang B, Kim H, Lee S, Won Y, Kaji I, Coffey RJ, Choi E, Goldenring JR. Dynamic tuft cell expansion during gastric metaplasia and dysplasia. J Pathol Clin Res 2024; 10:e352. [PMID: 38117182 PMCID: PMC10766036 DOI: 10.1002/cjp2.352] [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: 06/10/2023] [Revised: 11/14/2023] [Accepted: 11/17/2023] [Indexed: 12/21/2023]
Abstract
Tuft cells are chemosensory cells associated with luminal homeostasis, immune response, and tumorigenesis in the gastrointestinal tract. We aimed to elucidate alterations in tuft cell populations during gastric atrophy and tumorigenesis in humans with correlative comparison to relevant mouse models. Tuft cell distribution was determined in human stomachs from organ donors and in gastric pathologies including Ménétrier's disease, Helicobacter pylori gastritis, intestinal metaplasia (IM), and gastric tumors. Tuft cell populations were examined in Lrig1-KrasG12D , Mist1-KrasG12D , and MT-TGFα mice. Tuft cells were evenly distributed throughout the entire normal human stomach, primarily concentrated in the isthmal region in the fundus. Ménétrier's disease stomach showed increased tuft cells. Similarly, Lrig1-Kras mice and mice overexpressing TGFα showed marked foveolar hyperplasia and expanded tuft cell populations. Human stomach with IM or dysplasia also showed increased tuft cell numbers. Similarly, Mist1-Kras mice had increased numbers of tuft cells during metaplasia and dysplasia development. In human gastric cancers, tuft cells were rarely observed, but showed positive associations with well-differentiated lesions. In mouse gastric cancer xenografts, tuft cells were restricted to dysplastic well-differentiated mucinous cysts and were lost in less differentiated cancers. Taken together, tuft cell populations increased in atrophic human gastric pathologies, metaplasia, and dysplasia, but were decreased in gastric cancers. Similar findings were observed in mouse models, suggesting that, while tuft cells are associated with precancerous pathologies, their loss is most associated with the progression to invasive cancer.
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Affiliation(s)
- Bogun Jang
- Section of Surgical SciencesVanderbilt University Medical CenterNashvilleTNUSA
- Jeju National University College of MedicineJejuRepublic of Korea
- Department of PathologyJeju National University HospitalJejuRepublic of Korea
| | - Hyesung Kim
- Section of Surgical SciencesVanderbilt University Medical CenterNashvilleTNUSA
- Jeju National University College of MedicineJejuRepublic of Korea
- Department of Cell and Developmental BiologyVanderbilt UniversityNashvilleTNUSA
| | - Su‐Hyung Lee
- Section of Surgical SciencesVanderbilt University Medical CenterNashvilleTNUSA
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTNUSA
| | - Yoonkyung Won
- Section of Surgical SciencesVanderbilt University Medical CenterNashvilleTNUSA
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTNUSA
| | - Izumi Kaji
- Section of Surgical SciencesVanderbilt University Medical CenterNashvilleTNUSA
- Department of Cell and Developmental BiologyVanderbilt UniversityNashvilleTNUSA
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTNUSA
| | - Robert J Coffey
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTNUSA
- Department of Internal MedicineVanderbilt University Medical CenterNashvilleTNUSA
| | - Eunyoung Choi
- Section of Surgical SciencesVanderbilt University Medical CenterNashvilleTNUSA
- Department of Cell and Developmental BiologyVanderbilt UniversityNashvilleTNUSA
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTNUSA
| | - James R Goldenring
- Section of Surgical SciencesVanderbilt University Medical CenterNashvilleTNUSA
- Department of Cell and Developmental BiologyVanderbilt UniversityNashvilleTNUSA
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTNUSA
- Nashville VA Medical CenterNashvilleTNUSA
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21
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Ye L, Liu B, Huang J, Zhao X, Wang Y, Xu Y, Wang S. DCLK1 and its oncogenic functions: A promising therapeutic target for cancers. Life Sci 2024; 336:122294. [PMID: 38007147 DOI: 10.1016/j.lfs.2023.122294] [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: 09/26/2023] [Revised: 11/14/2023] [Accepted: 11/22/2023] [Indexed: 11/27/2023]
Abstract
Doublecortin-like kinase 1 (DCLK1), a significant constituent of the protein kinase superfamily and the doublecortin family, has been recognized as a prooncogenic factor that exhibits a strong association with the malignant progression and clinical prognosis of various cancers. DCLK1 serves as a stem cell marker that governs tumorigenesis, tumor cell reprogramming, and epithelial-mesenchymal transition. Multiple studies have indicated the capable of DCLK1 in regulating the DNA damage response and facilitating DNA damage repair. Additionally, DCLK1 is involved in the regulation of the immune microenvironment and the promotion of tumor immune evasion. Recently, DCLK1 has emerged as a promising therapeutic target for a multitude of cancers. Several small-molecule inhibitors of DCLK1 have been identified. Nevertheless, the biological roles of DCLK1 are mainly ambiguous, particularly with the disparities between its α- and β-form transcripts in the malignant progression of cancers, which impedes the development of more precisely targeted drugs. This article focuses on tumor stem cells, tumor epithelial-mesenchymal transition, the DNA damage response, and the tumor microenvironment to provide a comprehensive overview of the association between DCLK1 and tumor malignant progression, address unsolved questions and current challenges, and project future directions for targeting DCLK1 for the diagnosis and treatment of cancers.
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Affiliation(s)
- Liu Ye
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| | - Beibei Liu
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| | - Jingling Huang
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| | - Xiaolin Zhao
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| | - Yuan Wang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, PR China
| | - Yungen Xu
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
| | - Shuping Wang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, PR China.
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22
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Wu L, Chen M, Lin Y, Zeng B, Guo W, Chen L, Li Y, Yu L, Li J, Chen X, Zhang W, Li S, Cai W, Zhang K, Jin X, Huang J, Lin Q, Yang Y, Fu F, Wang C. Prognostic Value of Immunohistochemistry-based Subtyping Before and After Neoadjuvant Chemotherapy in Patients with Triple-negative Breast Cancer. Am J Surg Pathol 2024; 48:27-35. [PMID: 38117286 DOI: 10.1097/pas.0000000000002139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2023]
Abstract
To assess the predictive and prognostic value of a subtyping method based on immunohistochemistry in patients with triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NAC). This study included patients with TNBC treated with anthracycline- and taxane-based NAC and curative surgery. Immunohistochemical (IHC) subtyping was performed using core needle biopsy specimens before NAC (pre-NAC) and residual tumors after NAC (post-NAC). Logistic regression was performed to identify predictive biomarkers of pathological complete response (pCR). Invasive disease-free survival (iDFS), distant disease-free survival (DDFS), and overall survival (OS) were assessed using the log-rank test and Cox proportional hazards regression. A total of 230 patients were followed up for a median of 59 months. Clinical lymph node status and the pre-NAC subtype were independent predictors of pCR (P=0.006 and 0.005, respectively). The pre-NAC subtype was an independent prognostic factor for long-term survival (iDFS: P < 0.001, DDFS: P=0.010, and OS: P=0.044). Among patients with residual disease (RD) after NAC, approximately 45% of tumors changed their IHC subtype. Furthermore, the post-NAC subtype, but not the pre-NAC subtype, was strongly associated with the survival of patients with RD (iDFS: P < 0.001, DDFS: P=0.005, and OS: P=0.006). The IHC subtype predicted response to NAC and long-term survival in patients with early TNBC. In patients with RD, almost 45% of the tumors changed subtype after NAC. The IHC subtype should be considered when planning additional therapies pre- and post-NAC.
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23
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Dogra S, Elayapillai SP, Qu D, Pitts K, Filatenkov A, Houchen CW, Berry WL, Moxley K, Hannafon BN. Targeting doublecortin-like kinase 1 reveals a novel strategy to circumvent chemoresistance and metastasis in ovarian cancer. Cancer Lett 2023; 578:216437. [PMID: 37838282 PMCID: PMC10872611 DOI: 10.1016/j.canlet.2023.216437] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 10/02/2023] [Accepted: 10/05/2023] [Indexed: 10/16/2023]
Abstract
Ovarian cancer (OvCa) has a dismal prognosis because of its late-stage diagnosis and the emergence of chemoresistance. Doublecortin-like kinase 1 (DCLK1) is a serine/threonine kinase known to regulate cancer cell "stemness", epithelial-mesenchymal transition (EMT), and drug resistance. Here we show that DCLK1 is a druggable target that promotes chemoresistance and tumor progression of high-grade serous OvCa (HGSOC). Importantly, high DCLK1 expression significantly correlates with poor overall and progression-free survival in OvCa patients treated with platinum chemotherapy. DCLK1 expression was elevated in a subset of HGSOC cell lines in adherent (2D) and spheroid (3D) cultures, and the expression was further increased in cisplatin-resistant (CPR) spheroids relative to their sensitive controls. Using cisplatin-sensitive and resistant isogenic cell lines, pharmacologic inhibition (DCLK1-IN-1), and genetic manipulation, we demonstrate that DCLK1 inhibition was effective at re-sensitizing cells to cisplatin, reducing cell proliferation, migration, and invasion. Using kinase domain mutants, we demonstrate that DCLK1 kinase activity is critical for mediating CPR. The combination of cisplatin and DCLK1-IN-1 showed a synergistic cytotoxic effect against OvCa cells in 3D conditions. Targeted gene expression profiling revealed that DCLK1 inhibition in CPR OvCa spheroids significantly reduced TGFβ signaling, and EMT. We show in vivo efficacy of combined DCLK1 inhibition and cisplatin in significantly reducing tumor metastases. Our study shows that DCLK1 is a relevant target in OvCa and combined targeting of DCLK1 in combination with existing chemotherapy could be a novel therapeutic approach to overcome resistance and prevent OvCa recurrence.
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Affiliation(s)
- Samrita Dogra
- Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Sugantha Priya Elayapillai
- Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Dongfeng Qu
- Department of Medicine, Section of Digestive Diseases and Nutrition, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Kamille Pitts
- Department of Medicine, Section of Digestive Diseases and Nutrition, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Alexander Filatenkov
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Courtney W Houchen
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Medicine, Section of Digestive Diseases and Nutrition, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - William L Berry
- Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Katherine Moxley
- Oklahoma Cancer Specialists and Research Institute, Tulsa, OK, USA
| | - Bethany N Hannafon
- Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
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24
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Orsburn BC. Metabolomic, Proteomic, and Single-Cell Proteomic Analysis of Cancer Cells Treated with the KRAS G12D Inhibitor MRTX1133. J Proteome Res 2023; 22:3703-3713. [PMID: 37983312 PMCID: PMC10696623 DOI: 10.1021/acs.jproteome.3c00212] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Indexed: 11/22/2023]
Abstract
Mutations in KRAS are common drivers of human cancers and are often those with the poorest overall prognosis for patients. A recently developed compound, MRTX1133, has shown promise in inhibiting the activity of KRASG12D mutant proteins, which is one of the main drivers of pancreatic cancer. To better understand the mechanism of action of this compound, I performed both proteomics and metabolomics on four KRASG12D mutant pancreatic cancer cell lines. To obtain increased granularity in the proteomic observations, single-cell proteomics was successfully performed on two of these lines. Following quality filtering, a total of 1498 single cells were analyzed. From these cells, 3140 total proteins were identified with approximately 953 proteins quantified per cell. At 48 h of treatment, two distinct populations of cells can be observed based on the level of effectiveness of the drug in decreasing the total abundance of the KRAS protein in each respective cell, with results that are effectively masked in the bulk cell analysis. All mass spectrometry data and processed results are publicly available at www.massive.ucsd.edu at accessions PXD039597, PXD039601, and PXD039600.
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Affiliation(s)
- Benjamin C. Orsburn
- The Department of Pharmacology and
Molecular Sciences, The Johns Hopkins University
School of Medicine, Baltimore, Maryland 21205, United States
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25
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Jiang Z, Zheng X, Li M, Liu M. Improving the prognosis of pancreatic cancer: insights from epidemiology, genomic alterations, and therapeutic challenges. Front Med 2023; 17:1135-1169. [PMID: 38151666 DOI: 10.1007/s11684-023-1050-6] [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: 08/30/2023] [Accepted: 11/15/2023] [Indexed: 12/29/2023]
Abstract
Pancreatic cancer, notorious for its late diagnosis and aggressive progression, poses a substantial challenge owing to scarce treatment alternatives. This review endeavors to furnish a holistic insight into pancreatic cancer, encompassing its epidemiology, genomic characterization, risk factors, diagnosis, therapeutic strategies, and treatment resistance mechanisms. We delve into identifying risk factors, including genetic predisposition and environmental exposures, and explore recent research advancements in precursor lesions and molecular subtypes of pancreatic cancer. Additionally, we highlight the development and application of multi-omics approaches in pancreatic cancer research and discuss the latest combinations of pancreatic cancer biomarkers and their efficacy. We also dissect the primary mechanisms underlying treatment resistance in this malignancy, illustrating the latest therapeutic options and advancements in the field. Conclusively, we accentuate the urgent demand for more extensive research to enhance the prognosis for pancreatic cancer patients.
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Affiliation(s)
- Zhichen Jiang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- Department of General Surgery, Division of Gastroenterology and Pancreas, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China
| | - Xiaohao Zheng
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Min Li
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
| | - Mingyang Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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26
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Moore LL, Houchen CW. Epigenetic Landscape and Therapeutic Implication of Gene Isoforms of Doublecortin-Like Kinase 1 for Cancer Stem Cells. Int J Mol Sci 2023; 24:16407. [PMID: 38003596 PMCID: PMC10671580 DOI: 10.3390/ijms242216407] [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: 09/08/2023] [Revised: 11/13/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
While significant strides have been made in understanding cancer biology, the enhancement in patient survival is limited, underscoring the urgency for innovative strategies. Epigenetic modifications characterized by hereditary shifts in gene expression without changes to the DNA sequence play a critical role in producing alternative gene isoforms. When these processes go awry, they influence cancer onset, growth, spread, and cancer stemness. In this review, we delve into the epigenetic and isoform nuances of the protein kinase, doublecortin-like kinase 1 (DCLK1). Recognized as a hallmark of tumor stemness, DCLK1 plays a pivotal role in tumorigenesis, and DCLK1 isoforms, shaped by alternative promoter usage and splicing, can reveal potential therapeutic touchpoints. Our discussion centers on recent findings pertaining to the specific functions of DCLK1 isoforms and the prevailing understanding of its epigenetic regulation via its two distinct promoters. It is noteworthy that all DCLK1 isoforms retain their kinase domain, suggesting that their unique functionalities arise from non-kinase mechanisms. Consequently, our research has pivoted to drugs that specifically influence the epigenetic generation of these DCLK1 isoforms. We posit that a combined therapeutic approach, harnessing both the epigenetic regulators of specific DCLK1 isoforms and DCLK1-targeted drugs, may prove more effective than therapies that solely target DCLK1.
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Affiliation(s)
- Landon L. Moore
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Courtney W. Houchen
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
- Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
- The Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK 73104, USA
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27
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Wei Y, Liu M, Yen EY, Yao J, Nguyen PT, Wang X, Yang Z, Yousef A, Pan D, Jin Y, Theady MS, Park J, Cai Y, Takeda M, Vasquez M, Zhou Y, Zhao H, Viale A, Wang H, Zhao D, DePinho RA, Yao W, Ying H. KRAS inhibition activates an actionable CD24 'don't eat me' signal in pancreas cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.21.558891. [PMID: 37790498 PMCID: PMC10542501 DOI: 10.1101/2023.09.21.558891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/05/2023]
Abstract
KRAS G12C inhibitor (G12Ci) has produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment is therefore crucial. To better understand the tumor biology of the KRAS G12C allele and possible bypass mechanisms, we developed a novel autochthonous KRAS G12C -driven PDAC model. Compared to the classical KRAS G12D PDAC model, the G12C model exhibit slower tumor growth, yet similar histopathological and molecular features. Aligned with clinical experience, G12Ci treatment of KRAS G12C tumors produced modest impact despite stimulating a 'hot' tumor immune microenvironment. Immunoprofiling revealed that CD24, a 'do-not-eat-me' signal, is significantly upregulated on cancer cells upon G12Ci treatment. Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment. Similar findings were observed in KRAS G12D -driven PDAC. Our study reveals common and distinct oncogenic KRAS allele-specific biology and identifies a clinically actionable adaptive mechanism that may improve the efficacy of oncogenic KRAS inhibitor therapy in PDAC. Significance Lack of faithful preclinical models limits the exploration of resistance mechanisms to KRAS G12C inhibitor in PDAC. We generated an autochthonous KRAS G12C -driven PDAC model, which revealed allele-specific biology of the KRAS G12C during PDAC development. We identified CD24 as an actionable adaptive mechanisms in cancer cells induced upon KRAS G12C inhibition and blocking CD24 sensitizes PDAC to KRAS inhibitors in preclinical models.
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28
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Storz P. Roles of differently polarized macrophages in the initiation and progressionof pancreatic cancer. Front Immunol 2023; 14:1237711. [PMID: 37638028 PMCID: PMC10450961 DOI: 10.3389/fimmu.2023.1237711] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 07/24/2023] [Indexed: 08/29/2023] Open
Abstract
During development of pancreatic cancer macrophage-mediated inflammatory processes and the formation of cancerous lesions are tightly connected. Based on insight from mouse models we provide an overview on the functions of classically-activated pro-inflammatory and alternatively-activated anti-inflammatory macrophages in the initiation and progression of pancreatic cancer. We highlight their roles in earliest events of tumor initiation such as acinar-to-ductal metaplasia (ADM), organization of the fibrotic lesion microenvironment, and growth of low-grade (LG) lesions. We then discuss their roles as tumor-associated macrophages (TAM) in progression to high-grade (HG) lesions with a cancerous invasive phenotype and an immunosuppressive microenvironment. Another focus is on how targeting these macrophage populations can affect immunosuppression, fibrosis and responses to chemotherapy, and eventually how this knowledge could be used for novel therapy approaches for patients with pancreatic ductal adenocarcinoma (PDA).
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Affiliation(s)
- Peter Storz
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, United States
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Davoodvandi A, Rafiyan M, Asemi Z, Matini SA. An epigenetic modulator with promising therapeutic impacts against gastrointestinal cancers: A mechanistic review on microRNA-195. Pathol Res Pract 2023; 248:154680. [PMID: 37467635 DOI: 10.1016/j.prp.2023.154680] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/06/2023] [Accepted: 07/07/2023] [Indexed: 07/21/2023]
Abstract
Due to their high prevalence, gastrointestinal cancers are one of the key causes of cancer-related death globally. The development of drug-resistant cancer cell populations is a major factor in the high mortality rate, and it affects about half of all cancer patients. Because of advances in our understanding of cancer molecular biology, non-coding RNAs (ncRNAs) have emerged as critical factors in the initiation and development of gastrointestinal cancers. Gene expression can be controlled in several ways by ncRNAs, including through epigenetic changes, interactions between microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) and proteins, and the function of lncRNAs as miRNA precursors or pseudogenes. As lncRNAs may be detected in the blood, circulating ncRNAs have emerged as a promising new class of non-invasive cancer biomarkers for use in the detection, staging, and prognosis of gastrointestinal cancers, as well as in the prediction of therapy efficacy. In this review, we assessed the role lncRNAs play in the progression, and maintenance of colorectal cancer, and how they might be used as therapeutic targets in the future.
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Affiliation(s)
- Amirhossein Davoodvandi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, I.R. Iran.
| | - Mahdi Rafiyan
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, I.R. Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, I.R. Iran.
| | - Seyed Amirhassan Matini
- Department of Pathology, School of Medicine, Kashan University of Medical Sciences, Kashan, I.R. Iran.
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Vlajic K, Pennington Kluger H, Bie W, Merrill BJ, Nonn L, Kajdacsy-Balla A, Tyner AL. Appearance of tuft cells during prostate cancer progression. Oncogene 2023; 42:2374-2385. [PMID: 37386128 PMCID: PMC10374444 DOI: 10.1038/s41388-023-02743-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 05/19/2023] [Accepted: 06/05/2023] [Indexed: 07/01/2023]
Abstract
Tuft cells are chemosensory epithelial cells that increase in number following infection or injury to robustly activate the innate immune response to alleviate or promote disease. Recent studies of castration resistant prostate cancer and its subtype, neuroendocrine prostate cancer, revealed Pou2f3+ populations in mouse models. The transcription factor Pou2f3 is a master regulator of the tuft cell lineage. We show that tuft cells are upregulated early during prostate cancer development, and their numbers increase with progression. Cancer-associated tuft cells in the mouse prostate express DCLK1, COX1, COX2, while human tuft cells express COX1. Mouse and human tuft cells exhibit strong activation of signaling pathways including EGFR and SRC-family kinases. While DCLK1 is a mouse tuft cell marker, it is not present in human prostate tuft cells. Tuft cells that appear in mouse models of prostate cancer display genotype-specific tuft cell gene expression signatures. Using bioinformatic analysis tools and publicly available datasets, we characterized prostate tuft cells in aggressive disease and highlighted differences between tuft cell populations. Our findings indicate that tuft cells contribute to the prostate cancer microenvironment and may promote development of more advanced disease. Further research is needed to understand contributions of tuft cells to prostate cancer progression.
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Affiliation(s)
- Katarina Vlajic
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, 60607, USA
| | - Hannah Pennington Kluger
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, 60607, USA
| | - Wenjun Bie
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, 60607, USA
| | - Bradley J Merrill
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, 60607, USA
- The University of Illinois Cancer Center, Chicago, IL, 60607, USA
| | - Larisa Nonn
- The University of Illinois Cancer Center, Chicago, IL, 60607, USA
- The Department of Pathology, at the University of Illinois at Chicago, Chicago, IL, 60607, USA
| | - Andre Kajdacsy-Balla
- The University of Illinois Cancer Center, Chicago, IL, 60607, USA
- The Department of Pathology, at the University of Illinois at Chicago, Chicago, IL, 60607, USA
| | - Angela L Tyner
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, 60607, USA.
- The University of Illinois Cancer Center, Chicago, IL, 60607, USA.
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31
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Wei W, Zhang W, Wu S, Duan W, Wang Z. Advances in tuft cells, a chemosensory cell in sequential diseases of the pancreas. Biochim Biophys Acta Rev Cancer 2023; 1878:188911. [PMID: 37182665 DOI: 10.1016/j.bbcan.2023.188911] [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: 02/17/2023] [Accepted: 05/10/2023] [Indexed: 05/16/2023]
Abstract
Tuft cells are solitary chemosensory cells distributed mainly in hollow organs and detected in human and mouse pancreas precursor lesions of pancreatic cancer. Induced by inflammation and KRAS mutation, pancreatic acinar cell-derived tuft cells play a protective role in epithelium injury. The tumour suppression of tuft cells has been indicated in some studies. However, the function of tuft cells in pancreatic cancer remains unclear. In this review, we first introduce the definition of tuft cells and then review the relationship between tuft cells and pancreatic inflammation. In addition, we emphasized the role of tuft cells in the genesis and development of pancreatic cancers, especially the part of markers for tuft cell's doublecortin-like kinase 1 (DCLK1). Finally, we turn to the microscopic perspective and review the interactions between tuft cells and the microbiome in the pancreatic microenvironment. Overall, we describe the role of tuft cells in response to tissue damage and tumour progression in the pancreas. Nevertheless, the specific formation principle and the more detailed mechanism of action of tuft cells in the pancreas remain to be further explored.
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Affiliation(s)
- Wanzhen Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China
| | - Weifan Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China
| | - Shuai Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China
| | - Wanxing Duan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.
| | - Zheng Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.
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Marstrand-Daucé L, Lorenzo D, Chassac A, Nicole P, Couvelard A, Haumaitre C. Acinar-to-Ductal Metaplasia (ADM): On the Road to Pancreatic Intraepithelial Neoplasia (PanIN) and Pancreatic Cancer. Int J Mol Sci 2023; 24:9946. [PMID: 37373094 PMCID: PMC10298625 DOI: 10.3390/ijms24129946] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/02/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
Adult pancreatic acinar cells show high plasticity allowing them to change in their differentiation commitment. Pancreatic acinar-to-ductal metaplasia (ADM) is a cellular process in which the differentiated pancreatic acinar cells transform into duct-like cells. This process can occur as a result of cellular injury or inflammation in the pancreas. While ADM is a reversible process allowing pancreatic acinar regeneration, persistent inflammation or injury can lead to the development of pancreatic intraepithelial neoplasia (PanIN), which is a common precancerous lesion that precedes pancreatic ductal adenocarcinoma (PDAC). Several factors can contribute to the development of ADM and PanIN, including environmental factors such as obesity, chronic inflammation and genetic mutations. ADM is driven by extrinsic and intrinsic signaling. Here, we review the current knowledge on the cellular and molecular biology of ADM. Understanding the cellular and molecular mechanisms underlying ADM is critical for the development of new therapeutic strategies for pancreatitis and PDAC. Identifying the intermediate states and key molecules that regulate ADM initiation, maintenance and progression may help the development of novel preventive strategies for PDAC.
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Affiliation(s)
- Louis Marstrand-Daucé
- INSERM UMR1149, Inflammation Research Center (CRI), Université Paris Cité, 75018 Paris, France; (L.M.-D.); (D.L.); (A.C.); (P.N.); (A.C.)
| | - Diane Lorenzo
- INSERM UMR1149, Inflammation Research Center (CRI), Université Paris Cité, 75018 Paris, France; (L.M.-D.); (D.L.); (A.C.); (P.N.); (A.C.)
| | - Anaïs Chassac
- INSERM UMR1149, Inflammation Research Center (CRI), Université Paris Cité, 75018 Paris, France; (L.M.-D.); (D.L.); (A.C.); (P.N.); (A.C.)
- Department of Pathology, Bichat Hospital, Université Paris Cité, 75018 Paris, France
| | - Pascal Nicole
- INSERM UMR1149, Inflammation Research Center (CRI), Université Paris Cité, 75018 Paris, France; (L.M.-D.); (D.L.); (A.C.); (P.N.); (A.C.)
| | - Anne Couvelard
- INSERM UMR1149, Inflammation Research Center (CRI), Université Paris Cité, 75018 Paris, France; (L.M.-D.); (D.L.); (A.C.); (P.N.); (A.C.)
- Department of Pathology, Bichat Hospital, Université Paris Cité, 75018 Paris, France
| | - Cécile Haumaitre
- INSERM UMR1149, Inflammation Research Center (CRI), Université Paris Cité, 75018 Paris, France; (L.M.-D.); (D.L.); (A.C.); (P.N.); (A.C.)
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Yan R, Huang X, Liu H, Xiao Z, Liu J, An G, Ge Y. DCLK1 Drives EGFR-TKI-Acquired Resistance in Lung Adenocarcinoma by Remodeling the Epithelial-Mesenchymal Transition Status. Biomedicines 2023; 11:biomedicines11051490. [PMID: 37239162 DOI: 10.3390/biomedicines11051490] [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: 02/06/2023] [Revised: 05/11/2023] [Accepted: 05/17/2023] [Indexed: 05/28/2023] Open
Abstract
OBJECTIVE Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is a first-line treatment for lung adenocarcinoma with EGFR-sensitive mutations, but acquired resistance to EGFR-TKIs remains a problem in clinical practice. The development of epithelial-mesenchymal transition (EMT) is a critical mechanism that induces acquired resistance to TKIs. Reversing acquired resistance to EGFR-TKIs through targeting the key molecules driving EMT provides an alternative choice for patients. We, therefore, aimed to explore the role of doublecortin-like kinase 1 (DCLK1) as an EMT driver gene in the acquired resistance of lung adenocarcinoma to EGFR-TKIs. METHODS The IC50 of Gefitinib or Osimertinib in PC9/HCC827 cells was measured using a cell counting kit-8 (CCK8) assay. The expression levels of EMT-related genes in PC9 and HCC827 cells were detected using RT-PCR and Western blot. Cell migration and invasion abilities were assessed via a transwell assay. For the in vivo experiments, PC9 cells were subcutaneously injected into BALB/c nude mice to form tumors. Upon harvesting, tumor tissues were retained for RT-PCR, Western blot, and polychromatic fluorescence staining to detect biomarker changes in the EMT process. RESULTS Gefitinib-resistant PC9 (PC9/GR) and Osimertinib-resistant HCC827 (HCC827/OR) cells showed remarkable activation of EMT and enhanced migration and invasion abilities compared to TKI-sensitive cells. In addition, DCLK1 expression was markedly increased in EGFR-TKI-resistant lung adenocarcinoma cells. The targeted knockout of DCLK1 effectively reversed the EMT phenotype in TKI-resistant cells and improved EGFR-TKI sensitivity, which was further validated by the in vivo experiments. CONCLUSIONS DCLK1 facilitates acquired resistance to EGFR-TKI in lung adenocarcinoma by inducting EMT and accelerating the migration and invasion abilities of TKI-resistant cells.
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Affiliation(s)
- Rui Yan
- Beijing Chao-Yang Hospital Department of Oncology, Capital Medical University, 8 Gongren Tiyuchang Nanlu Road, Chaoyang Dist., Beijing 100020, China
| | - Xuying Huang
- Beijing Chao-Yang Hospital Department of Oncology, Capital Medical University, 8 Gongren Tiyuchang Nanlu Road, Chaoyang Dist., Beijing 100020, China
| | - Heshu Liu
- Beijing Chao-Yang Hospital Department of Oncology, Capital Medical University, 8 Gongren Tiyuchang Nanlu Road, Chaoyang Dist., Beijing 100020, China
| | - Zeru Xiao
- Beijing Chao-Yang Hospital Department of Oncology, Capital Medical University, 8 Gongren Tiyuchang Nanlu Road, Chaoyang Dist., Beijing 100020, China
| | - Jian Liu
- Beijing Chao-Yang Hospital Department of Oncology, Capital Medical University, 8 Gongren Tiyuchang Nanlu Road, Chaoyang Dist., Beijing 100020, China
| | - Guangyu An
- Beijing Chao-Yang Hospital Department of Oncology, Capital Medical University, 8 Gongren Tiyuchang Nanlu Road, Chaoyang Dist., Beijing 100020, China
| | - Yang Ge
- Beijing Chao-Yang Hospital Department of Oncology, Capital Medical University, 8 Gongren Tiyuchang Nanlu Road, Chaoyang Dist., Beijing 100020, China
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34
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Iqbal S, Rezaul Karim M, Yang DC, Mathiyalagan R, Chan Kang S. Tuft cells - the immunological interface and role in disease regulation. Int Immunopharmacol 2023; 118:110018. [PMID: 36989894 DOI: 10.1016/j.intimp.2023.110018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 02/09/2023] [Accepted: 03/07/2023] [Indexed: 03/29/2023]
Abstract
Tuft cells, also known as taste chemosensory cells, accumulate during parasite colonization or infection and have powerful immunomodulatory effects on substances that could be detrimental, as well as possible anti-inflammatory or antibacterial effects. Tuft cells are the primary source of interleukin (IL)-25. They trigger extra Innate lymphoid type-2 cells (ILC2) in the intestinal lamina propria to create cytokines (type 2); for instance, IL-13, which leads to an increase in IL-25. As tuft cells can produce biological effector molecules, such as IL-25 and eicosanoids involved in allergy (for example, cysteinyl leukotrienes and prostaglandin D2) and the neurotransmitter acetylcholine. Following parasite infection, tuft cells require transient receptor potential cation channel subfamily M member 5 (TRPM5)-dependent chemosensation to produce responses. Secretory tuft cells provide a physical mucus barrier against the external environment and therefore have vital defensive roles against diseases by supporting tissue maintenance and repair. In addition to recent research on tuft cells, more studies are required to understand the distribution, cell turnover, molecular characteristics, responses in various species, involvement in immunological function across tissues, and most importantly, the mechanism involved in the control of various diseases.
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Affiliation(s)
- Safia Iqbal
- Department of Biopharmaceutical Biotechnology, College of Life Science, Kyung Hee University, Yongin-si, Gyeonggi-do 17104, Korea; Department of Microbiology, Varendra Institute of Biosciences, Affiliated by Rajshahi University, Natore, Rajshahi, Bangladesh.
| | - Md Rezaul Karim
- Department of Biopharmaceutical Biotechnology, College of Life Science, Kyung Hee University, Yongin-si, Gyeonggi-do 17104, Korea; Department of Biotechnology and Genetic Engineering, Faculty of Biological Sciences, Islamic University, Kushtia 7003, Bangladesh.
| | - Deok-Chun Yang
- Department of Biopharmaceutical Biotechnology, College of Life Science, Kyung Hee University, Yongin-si, Gyeonggi-do 17104, Korea; Graduate School of Biotechnology, College of Life Science, Kyung Hee University, Yongin-si, Gyeonggi-do 17104, Korea.
| | - Ramya Mathiyalagan
- Graduate School of Biotechnology, College of Life Science, Kyung Hee University, Yongin-si, Gyeonggi-do 17104, Korea.
| | - Se Chan Kang
- Department of Biopharmaceutical Biotechnology, College of Life Science, Kyung Hee University, Yongin-si, Gyeonggi-do 17104, Korea; Graduate School of Biotechnology, College of Life Science, Kyung Hee University, Yongin-si, Gyeonggi-do 17104, Korea.
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35
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Yamazaki M, Hino S, Usuki S, Miyazaki Y, Oda T, Nakao M, Ito T, Yamagata K. YAP/BRD4-controlled ROR1 promotes tumor-initiating cells and hyperproliferation in pancreatic cancer. EMBO J 2023:e112614. [PMID: 37096681 DOI: 10.15252/embj.2022112614] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 03/23/2023] [Accepted: 03/29/2023] [Indexed: 04/26/2023] Open
Abstract
Tumor-initiating cells are major drivers of chemoresistance and attractive targets for cancer therapy, however, their identity in human pancreatic ductal adenocarcinoma (PDAC) and the key molecules underlying their traits remain poorly understood. Here, we show that a cellular subpopulation with partial epithelial-mesenchymal transition (EMT)-like signature marked by high expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) is the origin of heterogeneous tumor cells in PDAC. We demonstrate that ROR1 depletion suppresses tumor growth, recurrence after chemotherapy, and metastasis. Mechanistically, ROR1 induces the expression of Aurora kinase B (AURKB) by activating E2F through c-Myc to enhance PDAC proliferation. Furthermore, epigenomic analyses reveal that ROR1 is transcriptionally dependent on YAP/BRD4 binding at the enhancer region, and targeting this pathway reduces ROR1 expression and prevents PDAC growth. Collectively, our findings reveal a critical role for ROR1high cells as tumor-initiating cells and the functional importance of ROR1 in PDAC progression, thereby highlighting its therapeutic targetability.
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Affiliation(s)
- Masaya Yamazaki
- Department of Medical Biochemistry, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Shinjiro Hino
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| | - Shingo Usuki
- Liaison Laboratory Research Promotion Center, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| | - Yoshihiro Miyazaki
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba, Japan
| | - Tatsuya Oda
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba, Japan
| | - Mitsuyoshi Nakao
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| | - Takaaki Ito
- Department of Medical Technology, Faculty of Health Science, Kumamoto Health Science University, Kumamoto, Japan
| | - Kazuya Yamagata
- Department of Medical Biochemistry, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
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Liu H, Yan R, Xiao Z, Huang X, Yao J, Liu J, An G, Ge Y. Targeting DCLK1 attenuates tumor stemness and evokes antitumor immunity in triple-negative breast cancer by inhibiting IL-6/STAT3 signaling. Breast Cancer Res 2023; 25:43. [PMID: 37069669 PMCID: PMC10108533 DOI: 10.1186/s13058-023-01642-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 03/20/2023] [Indexed: 04/19/2023] Open
Abstract
Triple-negative breast cancer (TNBC) exhibits the poorest outcomes among breast cancer subtypes due to the high heterogeneity and a lasting scarcity of effectual treatments. Targeted therapies based on molecular subtypes of TNBC are critical step toward tailoring treatments to improve clinical outcomes. Gastrointestinal cancer stem cell (CSC) marker DCLK1 was reported to be highly expressed in stem cell-rich subtype of TNBC. Here, we firstly explored the impacts of DCLK1 on tumor cells as well as their immune microenvironment in TNBC and potential therapeutic strategies for TNBC patients with high DCLK1 expression. Our results disclosed that DCLK1 overexpression promoted, while knockout of DCLK1 suppressed the CSC-like traits of TNBC cells and resistance to chemotherapeutics. Besides, DCLK1 supported immune escape by inhibiting intratumoral cytotoxic T cell infiltration in TNBC and hence limited immune checkpoint inhibitors efficacy. Mechanistically, bioinformatics analysis revealed that IL-6/STAT3 signaling was significantly enriched in high DCLK1-expressing patients, and our results further revealed that DCLK1 enhanced IL-6 expression and STAT3 activation in TNBC cells, which finally gave rise to upregulated CSC traits and suppressed CD8+ T-cell activity. Inhibiting IL-6/STAT3 pathway by IL-6R antagonist, Tocilizumab or STAT3 inhibitor, S31-201 could abolish DCLK1-promoted malignant phenotypes of TNBC cells. Finally, DCLK1 was identified to be specifically and highly expressed in the mesenchymal-like subtype of TNBC and targeting DCLK1 could improve chemotherapy efficacy and activate antitumor immunity. Overall, our study revealed the potential clinical benefits of targeting DCLK1 in TNBC treatment.
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Affiliation(s)
- Heshu Liu
- Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China
| | - Rui Yan
- Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China
| | - Zeru Xiao
- Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China
| | - Xuying Huang
- Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China
| | - Jiannan Yao
- Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China
| | - Jian Liu
- Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China
| | - Guangyu An
- Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China
| | - Yang Ge
- Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China.
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37
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Kotas ME, O'Leary CE, Locksley RM. Tuft Cells: Context- and Tissue-Specific Programming for a Conserved Cell Lineage. ANNUAL REVIEW OF PATHOLOGY 2023; 18:311-335. [PMID: 36351364 PMCID: PMC10443898 DOI: 10.1146/annurev-pathol-042320-112212] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Tuft cells are found in tissues with distinct stem cell compartments, tissue architecture, and luminal exposures but converge on a shared transcriptional program, including expression of taste transduction signaling pathways. Here, we summarize seminal and recent findings on tuft cells, focusing on major categories of function-instigation of type 2 cytokine responses, orchestration of antimicrobial responses, and emerging roles in tissue repair-and describe tuft cell-derived molecules used to affect these functional programs. We review what is known about the development of tuft cells from epithelial progenitors under homeostatic conditions and during disease. Finally, we discuss evidence that immature, or nascent, tuft cells with potential for diverse functions are driven toward dominant effector programs by tissue- or perturbation-specific contextual cues, which may result in heterogeneous mature tuft cell phenotypes both within and between tissues.
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Affiliation(s)
- Maya E Kotas
- Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, California, USA
- Department of Medicine, University of California, San Francisco, California, USA
| | - Claire E O'Leary
- Department of Medicine, University of California, San Francisco, California, USA
- Current affiliation: Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Richard M Locksley
- Department of Medicine, University of California, San Francisco, California, USA
- Department of Microbiology and Immunology, University of California, San Francisco, California, USA;
- Howard Hughes Medical Institute, University of California, San Francisco, California, USA
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38
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Chung WC, Xu K. Notch signaling pathway in pancreatic tumorigenesis. Adv Cancer Res 2023. [DOI: 10.1016/bs.acr.2023.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2023]
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Rouzbahani E, Majidpoor J, Najafi S, Mortezaee K. Cancer stem cells in immunoregulation and bypassing anti-checkpoint therapy. Biomed Pharmacother 2022; 156:113906. [DOI: 10.1016/j.biopha.2022.113906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/16/2022] [Accepted: 10/19/2022] [Indexed: 11/26/2022] Open
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40
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Cave DD, Buonaiuto S, Sainz B, Fantuz M, Mangini M, Carrer A, Di Domenico A, Iavazzo TT, Andolfi G, Cortina C, Sevillano M, Heeschen C, Colonna V, Corona M, Cucciardi A, Di Guida M, Batlle E, De Luca A, Lonardo E. LAMC2 marks a tumor-initiating cell population with an aggressive signature in pancreatic cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:315. [PMID: 36289544 PMCID: PMC9609288 DOI: 10.1186/s13046-022-02516-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 10/09/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Tumor-initiating cells (TIC), also known as cancer stem cells, are considered a specific subpopulation of cells necessary for cancer initiation and metastasis; however, the mechanisms by which they acquire metastatic traits are not well understood. METHODS LAMC2 transcriptional levels were evaluated using publicly available transcriptome data sets, and LAMC2 immunohistochemistry was performed using a tissue microarray composed of PDAC and normal pancreas tissues. Silencing and tracing of LAMC2 was performed using lentiviral shRNA constructs and CRISPR/Cas9-mediated homologous recombination, respectively. The contribution of LAMC2 to PDAC tumorigenicity was explored in vitro by tumor cell invasion, migration, sphere-forming and organoids assays, and in vivo by tumor growth and metastatic assays. mRNA sequencing was performed to identify key cellular pathways upregulated in LAMC2 expressing cells. Metastatic spreading induced by LAMC2- expressing cells was blocked by pharmacological inhibition of transforming growth factor beta (TGF-β) signaling. RESULTS We report a LAMC2-expressing cell population, which is endowed with enhanced self-renewal capacity, and is sufficient for tumor initiation and differentiation, and drives metastasis. mRNA profiling of these cells indicates a prominent squamous signature, and differentially activated pathways critical for tumor growth and metastasis, including deregulation of the TGF-β signaling pathway. Treatment with Vactosertib, a new small molecule inhibitor of the TGF-β type I receptor (activin receptor-like kinase-5, ALK5), completely abrogated lung metastasis, primarily originating from LAMC2-expressing cells. CONCLUSIONS We have identified a highly metastatic subpopulation of TICs marked by LAMC2. Strategies aimed at targeting the LAMC2 population may be effective in reducing tumor aggressiveness in PDAC patients. Our results prompt further study of this TIC population in pancreatic cancer and exploration as a potential therapeutic target and/or biomarker.
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Affiliation(s)
- Donatella Delle Cave
- grid.5326.20000 0001 1940 4177Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR-IGB), 80131 Naples, Italy
| | - Silvia Buonaiuto
- grid.5326.20000 0001 1940 4177Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR-IGB), 80131 Naples, Italy
| | - Bruno Sainz
- grid.466793.90000 0004 1803 1972Department of Cancer Biology, Instituto de Investigaciones Biomedicas “Alberto Sols” (IIBM), CSIC-UAM, 28029 Madrid, Spain ,grid.420232.50000 0004 7643 3507Chronic Diseases and Cancer, Area 3-Instituto Ramon Y Cajal de Investigacion Sanitaria (IRYCIS), 28034 Madrid, Spain ,grid.510933.d0000 0004 8339 0058Centro de Investigación Biomédica en Red, Área Cáncer, CIBERONC, ISCIII, 28029 Madrid, Spain
| | - Marco Fantuz
- grid.5608.b0000 0004 1757 3470Department of Biology, University of Padova, 35129 Padova, Italy ,grid.428736.cVeneto Institute of Molecular Medicine (VIMM), 35129 Padova, Italy
| | - Maria Mangini
- grid.5326.20000 0001 1940 4177Institute for Experimental Endocrinology and Oncology, “G. Salvatore” (IEOS), Second Unit, Consiglio Nazionale Delle Ricerche (CNR), 801310 Naples, Italy
| | - Alessandro Carrer
- grid.5608.b0000 0004 1757 3470Department of Biology, University of Padova, 35129 Padova, Italy ,grid.428736.cVeneto Institute of Molecular Medicine (VIMM), 35129 Padova, Italy
| | - Annalisa Di Domenico
- grid.5326.20000 0001 1940 4177Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR-IGB), 80131 Naples, Italy
| | - Tea Teresa Iavazzo
- grid.5326.20000 0001 1940 4177Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR-IGB), 80131 Naples, Italy
| | - Gennaro Andolfi
- grid.5326.20000 0001 1940 4177Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR-IGB), 80131 Naples, Italy
| | - Carme Cortina
- grid.7722.00000 0001 1811 6966Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10, 08028 Barcelona, Spain ,grid.510933.d0000 0004 8339 0058Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 08028 Barcelona, Spain
| | - Marta Sevillano
- grid.7722.00000 0001 1811 6966Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10, 08028 Barcelona, Spain ,grid.510933.d0000 0004 8339 0058Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 08028 Barcelona, Spain
| | - Christopher Heeschen
- grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Vincenza Colonna
- grid.5326.20000 0001 1940 4177Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR-IGB), 80131 Naples, Italy
| | - Marco Corona
- grid.5326.20000 0001 1940 4177Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR-IGB), 80131 Naples, Italy
| | - Antonio Cucciardi
- grid.5326.20000 0001 1940 4177Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR-IGB), 80131 Naples, Italy
| | - Martina Di Guida
- grid.5326.20000 0001 1940 4177Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR-IGB), 80131 Naples, Italy
| | - Eduard Batlle
- grid.7722.00000 0001 1811 6966Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10, 08028 Barcelona, Spain ,grid.510933.d0000 0004 8339 0058Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 08028 Barcelona, Spain
| | - Annachiara De Luca
- grid.5326.20000 0001 1940 4177Institute for Experimental Endocrinology and Oncology, “G. Salvatore” (IEOS), Second Unit, Consiglio Nazionale Delle Ricerche (CNR), 801310 Naples, Italy
| | - Enza Lonardo
- grid.5326.20000 0001 1940 4177Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR-IGB), 80131 Naples, Italy
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Si M, Song Y, Wang X, Wang D, Liu X, Qu X, Song Z, Yu X. CXCL12/CXCR7/β-arrestin1 biased signal promotes epithelial-to-mesenchymal transition of colorectal cancer by repressing miRNAs through YAP1 nuclear translocation. Cell Biosci 2022; 12:171. [PMID: 36210463 PMCID: PMC9549625 DOI: 10.1186/s13578-022-00908-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 09/28/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Chemokine CXC motif receptor 7 (CXCR7) is an atypical G protein-coupled receptor (GPCR) that signals in a biased fashion. CXCL12/CXCR7 biased signal has been reported to play crucial roles in multiple stages of colorectal cancer (CRC). However, the mechanism of CXCL12/CXCR7 biased signal in promoting CRC progression and metastasis remains obscure. RESULTS We demonstrate that CXCR7 activation promotes EMT and upregulates the expression of Vimentin and doublecortin-like kinase 1 (DCLK1) in CRC cells with concurrent repression of miR-124-3p and miR-188-5p through YAP1 nuclear translocation. Cell transfection and luciferase assay prove that these miRNAs regulate EMT by targeting Vimentin and DCLK1. More importantly, CXCL12/CXCR7/β-arrestin1-mediated biased signal induces YAP1 nuclear translocation, which functions as a transcriptional repressor by interacting with Yin Yang 1 (YY1) and recruiting YY1 to the promoters of miR-124-3p and miR-188-5p. Pharmacological inhibitor of YAP1 suppresses EMT and tumor metastasis upon CXCR7 activation in vivo in tumor xenografts of nude mice and inflammatory colonic adenocarcinoma models. Clinically, the expression of CXCR7 is positively correlated with nuclear YAP1 levels and EMT markers. CONCLUSIONS Our studies reveal a novel mechanism and clinical significance of CXCL12/CXCR7 biased signal in promoting EMT and invasion in CRC progression. These findings highlight the potential of targeting YAP1 nuclear translocation in hampering CXCL12/CXCR7 biased signal-induced metastasis of colorectal cancer.
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Affiliation(s)
- Mahan Si
- grid.24696.3f0000 0004 0369 153XDepartment of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yujia Song
- grid.24696.3f0000 0004 0369 153XDepartment of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xiaohui Wang
- grid.24696.3f0000 0004 0369 153XDepartment of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Dong Wang
- grid.24696.3f0000 0004 0369 153XDepartment of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xiaohui Liu
- grid.24696.3f0000 0004 0369 153XDepartment of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xianjun Qu
- grid.24696.3f0000 0004 0369 153XDepartment of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Zhiyu Song
- grid.414011.10000 0004 1808 090XDepartment of Pharmacy, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, Henan China
| | - Xinfeng Yu
- grid.24696.3f0000 0004 0369 153XDepartment of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
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42
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Evan T, Wang VMY, Behrens A. The roles of intratumour heterogeneity in the biology and treatment of pancreatic ductal adenocarcinoma. Oncogene 2022; 41:4686-4695. [PMID: 36088504 PMCID: PMC9568427 DOI: 10.1038/s41388-022-02448-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 08/11/2022] [Accepted: 08/17/2022] [Indexed: 11/13/2022]
Abstract
Intratumour heterogeneity (ITH) has become an important focus of cancer research in recent years. ITH describes the cellular variation that enables tumour evolution, including tumour progression, metastasis and resistance to treatment. The selection and expansion of genetically distinct treatment-resistant cancer cell clones provides one explanation for treatment failure. However, tumour cell variation need not be genetically encoded. In pancreatic ductal adenocarcinoma (PDAC) in particular, the complex tumour microenvironment as well as crosstalk between tumour and stromal cells result in exceptionally variable tumour cell phenotypes that are also highly adaptable. In this review we discuss four different types of phenotypic heterogeneity within PDAC, from morphological to metabolic heterogeneity. We suggest that these different types of ITH are not independent, but, rather, can inform one another. Lastly, we highlight recent findings that suggest how therapeutic efforts may halt PDAC progression by constraining cellular heterogeneity.
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Affiliation(s)
- Theodore Evan
- Cancer Stem Cell Laboratory, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, SW3 6JB, UK
| | | | - Axel Behrens
- Cancer Stem Cell Laboratory, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, SW3 6JB, UK.
- Department of Surgery and Cancer, Imperial College London, London, SW7 2AZ, UK.
- CRUK Convergence Science Centre, Imperial College London, SW7 2AZ, London, UK.
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43
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Chhetri D, Vengadassalapathy S, Venkadassalapathy S, Balachandran V, Umapathy VR, Veeraraghavan VP, Jayaraman S, Patil S, Iyaswamy A, Palaniyandi K, Gnanasampanthapandian D. Pleiotropic effects of DCLK1 in cancer and cancer stem cells. Front Mol Biosci 2022; 9:965730. [PMID: 36250024 PMCID: PMC9560780 DOI: 10.3389/fmolb.2022.965730] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 08/12/2022] [Indexed: 12/02/2022] Open
Abstract
Doublecortin-like kinase 1 (DCLK1), a protein molecule, has been identified as a tumor stem cell marker in the cancer cells of gastrointestinal, pancreas, and human colon. DCLK1 expression in cancers, such as breast carcinoma, lung carcinoma, hepatic cell carcinoma, tuft cells, and human cholangiocarcinoma, has shown a way to target the DCLK1 gene and downregulate its expression. Several studies have discussed the inhibition of tumor cell proliferation along with neoplastic cell arrest when the DCLK1 gene, which is expressed in both cancer and normal cells, was targeted successfully. In addition, previous studies have shown that DCLK1 plays a vital role in various cancer metastases. The correlation of DCLK1 with numerous stem cell receptors, signaling pathways, and genes suggests its direct or an indirect role in promoting tumorigenesis. Moreover, the impact of DCLK1 was found to be related to the functioning of an oncogene. The downregulation of DCLK1 expression by using targeted strategies, such as embracing the use of siRNA, miRNA, CRISPR/Cas9 technology, nanomolecules, specific monoclonal antibodies, and silencing the pathways regulated by DCLK1, has shown promising results in both in vitro and in vivo studies on gastrointestinal (GI) cancers. In this review, we will discuss about the present understanding of DCLK1 and its role in the progression of GI cancer and metastasis.
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Affiliation(s)
- Dibyashree Chhetri
- Cancer Science Laboratory, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Chennai, India
| | - Srinivasan Vengadassalapathy
- Department of Pharmacology, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Chennai, India
| | | | - Varadharaju Balachandran
- Department of Physiology, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Vidhya Rekha Umapathy
- Department of Public Health Dentistry, Sree Balaji Dental College and Hospital, Chennai, India
| | - Vishnu Priya Veeraraghavan
- Department of Biochemistry, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Selvaraj Jayaraman
- Department of Biochemistry, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Shankargouda Patil
- College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UT, United States
| | - Ashok Iyaswamy
- Centre for Parkinsons Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
| | - Kanagaraj Palaniyandi
- Cancer Science Laboratory, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Chennai, India
- *Correspondence: Kanagaraj Palaniyandi, ; Dhanavathy Gnanasampanthapandian,
| | - Dhanavathy Gnanasampanthapandian
- Cancer Science Laboratory, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Chennai, India
- *Correspondence: Kanagaraj Palaniyandi, ; Dhanavathy Gnanasampanthapandian,
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Lineage Tracing and Molecular Real-Time Imaging of Cancer Stem Cells. BIOSENSORS 2022; 12:bios12090703. [PMID: 36140088 PMCID: PMC9496355 DOI: 10.3390/bios12090703] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 11/17/2022]
Abstract
The cancer stem cells (CSC) are the roots of cancer. The CSC hypothesis may provide a model to explain the tumor cell heterogeneity. Understand the biological mechanism of CSC will help the early detection and cure of cancer. The discovery of the dynamic changes in CSC will be possible by the using of bio-engineering techniques-lineage tracing. However, it is difficult to obtain real-time, continuous, and dynamic live-imaging information using the traditional approaches that take snapshots of time points from different animals. The goal of molecular imaging is to monitor the in situ, continuous molecular changes of cells in vivo. Therefore, the most advanced bioengineering lineage tracing approach, while using a variety of molecular detection methods, will maximize the presentation of CSC. In this review, we first introduce the method of lineage tracing, and then introduce the various components of molecular images to dynamic detect the CSC. Finally, we analyze the current situation and look forward the future of CSC detection.
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Panieri E, Pinho SA, Afonso GJM, Oliveira PJ, Cunha-Oliveira T, Saso L. NRF2 and Mitochondrial Function in Cancer and Cancer Stem Cells. Cells 2022; 11:cells11152401. [PMID: 35954245 PMCID: PMC9367715 DOI: 10.3390/cells11152401] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 12/21/2022] Open
Abstract
The NRF2–KEAP1 system is a fundamental component of the cellular response that controls a great variety of transcriptional targets that are mainly involved in the regulation of redox homeostasis and multiple cytoprotective mechanisms that confer adaptation to the stress conditions. The pleiotropic response orchestrated by NRF2 is particularly relevant in the context of oncogenic activation, wherein this transcription factor acts as a key driver of tumor progression and cancer cells’ resistance to treatment. For this reason, NRF2 has emerged as a promising therapeutic target in cancer cells, stimulating extensive research aimed at the identification of natural, as well as chemical, NRF2 inhibitors. Excitingly, the influence of NRF2 on cancer cells’ biology extends far beyond its mere antioxidant function and rather encompasses a functional crosstalk with the mitochondrial network that can influence crucial aspects of mitochondrial homeostasis, including biogenesis, oxidative phosphorylation, metabolic reprogramming, and mitophagy. In the present review, we summarize the current knowledge of the reciprocal interrelation between NRF2 and mitochondria, with a focus on malignant tumors and cancer stem cells.
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Affiliation(s)
- Emiliano Panieri
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, 00185 Rome, Italy
- Section of Hazardous Substances, Environmental Education and Training for the Technical Coordination of Management Activities (DGTEC), Italian Institute for Environmental Protection and Research, 00144 Rome, Italy
- Correspondence: (E.P.); (T.C.-O.); Tel.: +39-06-5007-2131 (E.P.); +351-231249195 (T.C.-O.)
| | - Sónia A. Pinho
- CNC—Center for Neuroscience and Cell Biology, CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- IIIUC—Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
- PhD Programme in Experimental Biology and Biomedicine (PDBEB), IIIUC—Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
| | - Gonçalo J. M. Afonso
- CNC—Center for Neuroscience and Cell Biology, CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- IIIUC—Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
- PhD Programme in Experimental Biology and Biomedicine (PDBEB), IIIUC—Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
| | - Paulo J. Oliveira
- CNC—Center for Neuroscience and Cell Biology, CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- IIIUC—Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
| | - Teresa Cunha-Oliveira
- CNC—Center for Neuroscience and Cell Biology, CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- IIIUC—Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
- Correspondence: (E.P.); (T.C.-O.); Tel.: +39-06-5007-2131 (E.P.); +351-231249195 (T.C.-O.)
| | - Luciano Saso
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, 00185 Rome, Italy
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Han X, Zhang W, Gao H, Li T, Xu H, Li H, Li P, Wang X, Yu X, Wang W, Liu L. Neoadjuvant chemotherapy endows CD9 with prognostic value that differs between tumor and stromal areas in patients with pancreatic cancer. J Clin Lab Anal 2022; 36:e24517. [PMID: 35622458 PMCID: PMC9279986 DOI: 10.1002/jcla.24517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 04/13/2022] [Accepted: 05/12/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND The selective pressure imposed by chemotherapy creates a barrier to tumor eradication and an opportunity for metastasis and recurrence. As a newly discovered stemness marker of pancreatic ductal adenocarcinoma (PDAC), the impact of CD9 on tumor progression and patient's prognosis remain controversial. METHODS A total of 179 and 211 PDAC patients who underwent surgical resection with or without neoadjuvant chemotherapy, respectively, were recruited for immunohistochemical analyses of CD9 expression in both tumor and stromal areas prior to statistical analyses to determine the prognostic impact and predictive accuracy of CD9. RESULTS The relationship between CD9 and prognostic indicators was not significant in the non-neoadjuvant group. Nevertheless, CD9 expression in both tumor (T-CD9) and stromal areas (S-CD9) was significantly correlated with the clinicopathological features in the neoadjuvant group. High levels of T-CD9 were significantly associated with worse OS (p = 0.005) and RFS (p = 0.007), while positive S-CD9 showed the opposite results (OS: p = 0.024; RFS: p = 0.008). Cox regression analyses identified CD9 in both areas as an independent prognostic factor. The T&S-CD9 risk-level system was used to stratify patients with different survival levels. The combination of T&S-CD9 risk level and TNM stage were accurate predictors of OS (C-index: 0.676; AIC: 512.51) and RFS (C-index: 0.680; AIC: 519.53). The calibration curve of the nomogram composed of the combined parameters showed excellent predictive consistency for 1-year RFS. These results were verified using a validation cohort. CONCLUSION Neoadjuvant chemotherapy endows CD9 with a significant prognostic value that differs between tumor and stromal areas in patients with pancreatic cancer.
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Affiliation(s)
- Xuan Han
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Wu‐Hu Zhang
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - He‐Li Gao
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Tian‐Jiao Li
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Hua‐Xiang Xu
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Hao Li
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Peng‐Cheng Li
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Xu Wang
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Xian‐Jun Yu
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Wen‐Quan Wang
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Liang Liu
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
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Kalantari E, Razmi M, Tajik F, Asadi-Lari M, Ghods R, Madjd Z. Oncogenic functions and clinical significances of DCLK1 isoforms in colorectal cancer: a systematic review and meta-analysis. Cancer Cell Int 2022; 22:217. [PMID: 35717205 PMCID: PMC9206744 DOI: 10.1186/s12935-022-02632-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 06/06/2022] [Indexed: 12/24/2022] Open
Abstract
Background The oncogenic role of doublecortin-like kinase 1 (DCLK1) as a putative cancer stem cell (CSC) marker has been clarified in colorectal cancer (CRC). Isoform-specific functions of DCLK1 have shed new light on different functions of DCLK1 short (DCLK1-S) and DCLK1 long (DCLK1-L) isoforms in tumor initiation, growth, and metastasis. Therefore, the current systematic review and meta-analysis aimed to review the available in vitro, in vivo, and clinical evidence on the oncogenic roles and clinical significance of DCLK1 isoforms in colorectal cancer. Methods The literature databases of PubMed, Scopus, ISI Web of Science, and Embase were searched to identify eligible articles. The description characteristics of in vitro and pre-clinical studies were extracted from identified reports. In addition, hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were recorded to determine the relationships between DCLK1-L and DCLK1-S expression and prognostic outcomes in patients with CRC. Results Both in vitro and in vivo evidence have emphasized the potential oncogenic functions of DCLK1 in tumor initiation, self-renewal ability, tumor invasion, epithelial-mesenchymal transition (EMT), and metastasis. However, the anti-DCLK1 antibodies generally utilized in these studies could detect sequence homology epitopes of both isoforms. Recent limited isoform-specific evidence has strongly supported the significant positive expression and rather oncogenic efficacy of DCLK1-S in tumorigenesis, EMT, and invasion compared with DCLK1-L in human CRC cell lines. Our meta-analysis findings of limited clinical studies indicated that only overexpression of DCLK1-S is associated with worse overall survival (OS) (HR = 7.930, 95% CI 2.252–27.924, p = 0.001). Increased expression of both DCLK1-S (HR = 1.610, 95% CI 1.020–2.541, p = 0.041) and DCLK1-L (HR = 5.890, 95% CI 1.219–28.453, p = 0.027) isoforms was closely associated with worse DSS/CSS in CRC patients. Furthermore, the high expression of DCLK1-S was found to be associated with poor DFS/RFS/PFS (HR = 1.913, 95% CI 1.230–2.973, p = 0.004). Conclusions The current findings strongly supported that the DCLK1-S isoform may play a crucial role in the invasion, aggressive tumor behavior, and worsened survival outcomes of CRC patients. However, further critical investigations related to the potential preclinical and clinical utilities of DCLK1-S as a specific CRC-CSC marker are warranted. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02632-9.
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Affiliation(s)
- Elham Kalantari
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Mahdieh Razmi
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Fatemeh Tajik
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Mohsen Asadi-Lari
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran.,Department of Epidemiology, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Roya Ghods
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran. .,Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran.
| | - Zahra Madjd
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran. .,Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran.
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48
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Jiang T, Wei F, Xie K. Clinical significance of pancreatic ductal metaplasia. J Pathol 2022; 257:125-139. [PMID: 35170758 DOI: 10.1002/path.5883] [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: 11/21/2021] [Revised: 02/06/2022] [Accepted: 02/14/2022] [Indexed: 11/08/2022]
Abstract
Pancreatic ductal metaplasia (PDM) is the stepwise replacement of differentiated somatic cells with ductal or ductal-like cells in the pancreas. PDM is usually triggered by cellular and environmental insults. PDM development may involve all cell lineages of the pancreas, and acinar cells with the highest plasticity are the major source of PDM. Pancreatic progenitor cells are also involved as cells of origin or transitional intermediates. PDM is heterogeneous at the histological, cellular, and molecular levels and only certain subsets of PDM develop further into pancreatic intraepithelial neoplasia (PanIN) and then pancreatic ductal adenocarcinoma (PDAC). The formation and evolution of PDM is regulated at the cellular and molecular levels through a complex network of signaling pathways. The key molecular mechanisms that drive PDM formation and its progression into PanIN/PDAC remain unclear, but represent key targets for reversing or inhibiting PDM. Alternatively, PDM could be a source of pancreas regeneration, including both exocrine and endocrine components. Cellular aging and apoptosis are obstacles to PDM-to-PanIN progression or pancreas regeneration. Functional identification of the cellular and molecular events driving senescence and apoptosis in PDM and its progression would help not only to restrict the development of PDM into PanIN/PDAC, but may also facilitate pancreatic regeneration. This review systematically assesses recent advances in the understanding of PDM physiology and pathology, with a focus on its implications for enhancing regeneration and prevention of cancer. © 2022 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Tingting Jiang
- Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, PR China
- Department of Pathology, The South China University of Technology School of Medicine, Guangzhou, PR China
| | - Fang Wei
- Institute of Digestive Diseases Research, The South China University of Technology School of Medicine, Guangzhou, PR China
| | - Keping Xie
- Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, PR China
- Department of Pathology, The South China University of Technology School of Medicine, Guangzhou, PR China
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Koltai T, Reshkin SJ, Carvalho TMA, Di Molfetta D, Greco MR, Alfarouk KO, Cardone RA. Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma: A Physiopathologic and Pharmacologic Review. Cancers (Basel) 2022; 14:2486. [PMID: 35626089 PMCID: PMC9139729 DOI: 10.3390/cancers14102486] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a poor prognosis and inadequate response to treatment. Many factors contribute to this therapeutic failure: lack of symptoms until the tumor reaches an advanced stage, leading to late diagnosis; early lymphatic and hematic spread; advanced age of patients; important development of a pro-tumoral and hyperfibrotic stroma; high genetic and metabolic heterogeneity; poor vascular supply; a highly acidic matrix; extreme hypoxia; and early development of resistance to the available therapeutic options. In most cases, the disease is silent for a long time, andwhen it does become symptomatic, it is too late for ablative surgery; this is one of the major reasons explaining the short survival associated with the disease. Even when surgery is possible, relapsesare frequent, andthe causes of this devastating picture are the low efficacy ofand early resistance to all known chemotherapeutic treatments. Thus, it is imperative to analyze the roots of this resistance in order to improve the benefits of therapy. PDAC chemoresistance is the final product of different, but to some extent, interconnected factors. Surgery, being the most adequate treatment for pancreatic cancer and the only one that in a few selected cases can achieve longer survival, is only possible in less than 20% of patients. Thus, the treatment burden relies on chemotherapy in mostcases. While the FOLFIRINOX scheme has a slightly longer overall survival, it also produces many more adverse eventsso that gemcitabine is still considered the first choice for treatment, especially in combination with other compounds/agents. This review discusses the multiple causes of gemcitabine resistance in PDAC.
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Affiliation(s)
| | - Stephan Joel Reshkin
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Tiago M. A. Carvalho
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Daria Di Molfetta
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Khalid Omer Alfarouk
- Zamzam Research Center, Zamzam University College, Khartoum 11123, Sudan;
- Alfarouk Biomedical Research LLC, Temple Terrace, FL 33617, USA
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
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50
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Wang D, Wang X, Song Y, Si M, Sun Y, Liu X, Cui S, Qu X, Yu X. Exosomal miR-146a-5p and miR-155-5p promote CXCL12/CXCR7-induced metastasis of colorectal cancer by crosstalk with cancer-associated fibroblasts. Cell Death Dis 2022; 13:380. [PMID: 35443745 PMCID: PMC9021302 DOI: 10.1038/s41419-022-04825-6] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 03/29/2022] [Accepted: 04/04/2022] [Indexed: 12/13/2022]
Abstract
C-X-C motif chemokine receptor 7 (CXCR7) is a newly discovered atypical chemokine receptor that binds to C-X-C motif chemokine ligand 12 (CXCL12) with higher affinity than CXCR4 and is associated with the metastasis of colorectal cancer (CRC). Cancer-associated fibroblasts (CAFs) have been known to promote tumor progression. However, whether CAFs are involved in CXCR7-mediated metastasis of CRC remains elusive. We found a significant positive correlation between CXCR7 expression and CAF activation markers in colonic tissues from clinical specimens and in villin-CXCR7 transgenic mice. RNA sequencing revealed a coordinated increase in the levels of miR-146a-5p and miR-155-5p in CXCR7-overexpressing CRC cells and their exosomes. Importantly, these CRC cell-derived miR-146a-5p and miR-155-5p could be uptaken by CAFs via exosomes and promote the activation of CAFs through JAK2–STAT3/NF-κB signaling by targeting suppressor of cytokine signaling 1 (SOCS1) and zinc finger and BTB domain containing 2 (ZBTB2). Reciprocally, activated CAFs further potently enhanced the invasive capacity of CRC cells. Mechanistically, CAFs transfected with miR-146a-5p and miR-155-5p exhibited a robust increase in the levels of inflammatory cytokines interleukin-6, tumor necrosis factor-α, transforming growth factor-β, and CXCL12, which trigger the epithelial–mesenchymal transition and pro-metastatic switch of CRC cells. More importantly, the activation of CAFs by miR-146a-5p and miR-155-5p facilitated tumor formation and lung metastasis of CRC in vivo using tumor xenograft models. Our work provides novel insights into CXCR7-mediated CRC metastasis from tumor–stroma interaction and serum exosomal miR-146a-5p and miR-155-5p could serve as potential biomarkers and therapeutic targets for inhibiting CRC metastasis.
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Affiliation(s)
- Dong Wang
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xiaohui Wang
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Yujia Song
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Mahan Si
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yuqi Sun
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xiaohui Liu
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Shuxiang Cui
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China
| | - Xianjun Qu
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xinfeng Yu
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
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