1
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Guetter S, König C, Koerkel-Qu H, Markiewicz A, Scheitler S, Katzer M, Berneburg M, Renner P, Cucuruz B, Guttenberger L, Naimer V, Weidele K, Treitschke S, Werno C, Jaser H, Bargmann T, Braun A, Weber F, Evert K, Rochwarger A, Schürch CM, Limm K, Oefner PJ, Rachel R, Baumann F, Warfsmann J, Schmidleithner L, Guetter K, Mohammadi P, Ulmer A, Haferkamp S, Klein CA, Werner-Klein M. MCSP + metastasis founder cells activate immunosuppression early in human melanoma metastatic colonization. NATURE CANCER 2025:10.1038/s43018-025-00963-w. [PMID: 40379833 DOI: 10.1038/s43018-025-00963-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 04/01/2025] [Indexed: 05/19/2025]
Abstract
To investigate the early, poorly understood events driving metastatic progression, we searched for the earliest detectable disseminated cancer cells (DCCs), also often referred to as disseminated tumor cells (DTCs), in sentinel lymph node (SLN) biopsies of 492 patients with stage I-III melanoma. Using micromanipulator-assisted isolation of rare DCCs, single-cell mRNA and DNA sequencing, codetection by indexing immunofluorescence imaging and survival analysis, we identified melanoma-associated chondroitin sulfate proteoglycan (MCSP)+ melanoma cells as metastasis founder cells (MFCs). We found that DCCs entering SLNs predominantly exhibited a transitory phenotype that, upon interferon-γ exposure triggered by CD8 T cells, dedifferentiated into a neural-crest-like phenotype. This was accompanied by increased production of small extracellular vesicles (sEVs) carrying the immunomodulatory proteins CD155 and CD276 but rarely programmed cell death protein 1 ligand 1. The sEVs suppressed CD8 T cell proliferation and function, facilitating colony formation. Targeting MCSP+ MFCs or their immune escape mechanisms could be key to curing melanoma early by preventing manifestation of metastasis.
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Affiliation(s)
- Severin Guetter
- Experimental Medicine and Therapy Research, University of Regensburg, Regensburg, Germany
| | - Courtney König
- Experimental Medicine and Therapy Research, University of Regensburg, Regensburg, Germany
| | - Huiqin Koerkel-Qu
- Experimental Medicine and Therapy Research, University of Regensburg, Regensburg, Germany
| | - Aleksandra Markiewicz
- Experimental Medicine and Therapy Research, University of Regensburg, Regensburg, Germany
| | - Sebastian Scheitler
- Experimental Medicine and Therapy Research, University of Regensburg, Regensburg, Germany
| | - Marie Katzer
- Department of Dermatology, University Medical Center Regensburg, Regensburg, Germany
| | - Mark Berneburg
- Department of Dermatology, University Medical Center Regensburg, Regensburg, Germany
| | - Philipp Renner
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Beatrix Cucuruz
- Department of Vascular Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Leonhard Guttenberger
- Experimental Medicine and Therapy Research, University of Regensburg, Regensburg, Germany
| | - Veronika Naimer
- Experimental Medicine and Therapy Research, University of Regensburg, Regensburg, Germany
| | - Kathrin Weidele
- Division of Personalized Tumor Therapy, Fraunhofer Institute for Toxicology and Experimental Medicine, Regensburg, Germany
| | - Steffi Treitschke
- Division of Personalized Tumor Therapy, Fraunhofer Institute for Toxicology and Experimental Medicine, Regensburg, Germany
| | - Christian Werno
- Division of Personalized Tumor Therapy, Fraunhofer Institute for Toxicology and Experimental Medicine, Regensburg, Germany
| | - Hanna Jaser
- Experimental Medicine and Therapy Research, University of Regensburg, Regensburg, Germany
| | - Tonia Bargmann
- Preclinical Pharmacology and Toxicology, Fraunhofer Institute for Toxicology and Experimental Medicine ITEM member of Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) in the German Center for Lung Research (DZL), Hannover, Germany
| | - Armin Braun
- Preclinical Pharmacology and Toxicology, Fraunhofer Institute for Toxicology and Experimental Medicine ITEM member of Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) in the German Center for Lung Research (DZL), Hannover, Germany
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - Florian Weber
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Katja Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Alexander Rochwarger
- Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany
| | - Christian M Schürch
- Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany
| | - Katharina Limm
- Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
| | - Peter J Oefner
- Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
| | - Reinhard Rachel
- Center for Electron Microscopy, University of Regensburg, Regensburg, Germany
| | - Felix Baumann
- Department of Pharmaceutical Technology, University of Regensburg, Regensburg, Germany
| | - Jens Warfsmann
- Division of Personalized Tumor Therapy, Fraunhofer Institute for Toxicology and Experimental Medicine, Regensburg, Germany
| | - Lisa Schmidleithner
- Leibniz Institute for Immunotherapy, University Hospital Regensburg, Regensburg, Germany
| | - Kathrin Guetter
- Leibniz Institute for Immunotherapy, University Hospital Regensburg, Regensburg, Germany
| | - Parvaneh Mohammadi
- Experimental Medicine and Therapy Research, University of Regensburg, Regensburg, Germany
| | - Anja Ulmer
- Department of Dermatology, University of Tübingen, Tübingen, Germany
| | - Sebastian Haferkamp
- Department of Dermatology, University Medical Center Regensburg, Regensburg, Germany
| | - Christoph A Klein
- Experimental Medicine and Therapy Research, University of Regensburg, Regensburg, Germany.
- Division of Personalized Tumor Therapy, Fraunhofer Institute for Toxicology and Experimental Medicine, Regensburg, Germany.
| | - Melanie Werner-Klein
- Experimental Medicine and Therapy Research, University of Regensburg, Regensburg, Germany.
- Leibniz Institute for Immunotherapy, University Hospital Regensburg, Regensburg, Germany.
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2
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Nguyen LV, Eyal-Lubling Y, Guerrero-Romero D, Kronheim S, Chin SF, Manzano Garcia R, Sammut SJ, Lerda G, Lui AJW, Bardwell HA, Greenwood W, Shin HJ, Masina R, Kania K, Bruna A, Esmaeilishirazifard E, Kolyvas EA, Aparicio S, Rueda OM, Caldas C. Fitness and transcriptional plasticity of human breast cancer single-cell-derived clones. Cell Rep 2025; 44:115699. [PMID: 40359107 DOI: 10.1016/j.celrep.2025.115699] [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: 11/13/2024] [Revised: 03/12/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
Clonal fitness and plasticity drive cancer heterogeneity. We used expressed lentiviral-based cellular barcodes combined with single-cell RNA sequencing to associate single-cell profiles with in vivo clonal growth. This generated a significant resource of growth measurements from over 20,000 single-cell-derived clones in 110 xenografts from 26 patient-derived breast cancer xenograft models. 167,375 single-cell RNA profiles were obtained from 5 models and revealed that rare propagating clones display a highly conserved model-specific differentiation program with reproducible regeneration of the entire transcriptomic landscape of the original xenograft. In 2 models of basal breast cancer, propagating clones demonstrated remarkable transcriptional plasticity at single-cell resolution. Dichotomous cell populations with different clonal growth properties, signaling pathways, and metabolic programs were characterized. By directly linking clonal growth with single-cell transcriptomes, these findings provide a profound understanding of clonal fitness and plasticity with implications for cancer biology and therapy.
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Affiliation(s)
- Long V Nguyen
- Department of Clinical Biochemistry and Institute of Metabolic Science, School of Clinical Medicine, University of Cambridge, Cambridge, UK; Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
| | | | | | - Sarah Kronheim
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | | | | | - Stephen-John Sammut
- Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK; The Royal Marsden Hospital NHS Foundation Trust, London, UK
| | - Giulia Lerda
- Cancer Research UK Cambridge Institute, Cambridge, UK; Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK; The Royal Marsden Hospital NHS Foundation Trust, London, UK
| | - Allan J W Lui
- Cancer Research UK Cambridge Institute, Cambridge, UK
| | | | | | - Hee Jin Shin
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | | | | | - Alejandra Bruna
- Centre for Paediatric Oncology Experimental Medicine, Centre for Cancer Evolution: Molecular Pathology Division, The Institute of Cancer Research, Sutton, UK
| | | | | | - Samuel Aparicio
- Department of Molecular Oncology, BC Cancer Research Institute, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Oscar M Rueda
- MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
| | - Carlos Caldas
- Department of Clinical Biochemistry and Institute of Metabolic Science, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
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3
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Pagliari F, Tirinato L, Di Fabrizio E. Raman spectroscopies for cancer research and clinical applications: a focus on cancer stem cells. Stem Cells 2025; 43:sxae084. [PMID: 39949042 DOI: 10.1093/stmcls/sxae084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 11/20/2024] [Indexed: 04/23/2025]
Abstract
Over the last 2 decades, research has increasingly focused on cancer stem cells (CSCs), considered responsible for tumor formation, resistance to therapies, and relapse. The traditional "static" CSC model used to describe tumor heterogeneity has been challenged by the evidence of CSC dynamic nature and plasticity. A comprehensive understanding of the mechanisms underlying this plasticity, and the capacity to unambiguously identify cancer markers to precisely target CSCs are crucial aspects for advancing cancer research and introducing more effective treatment strategies. In this context, Raman spectroscopy (RS) and specific Raman schemes, including CARS, SRS, SERS, have emerged as innovative tools for molecular analyses both in vitro and in vivo. In fact, these techniques have demonstrated considerable potential in the field of cancer detection, as well as in intraoperative settings, thanks to their label-free nature and minimal invasiveness. However, the RS integration in pre-clinical and clinical applications, particularly in the CSC field, remains limited. This review provides a concise overview of the historical development of RS and its advantages. Then, after introducing the CSC features and the challenges in targeting them with traditional methods, we review and discuss the current literature about the application of RS for revealing and characterizing CSCs and their inherent plasticity, including a brief paragraph about the integration of artificial intelligence with RS. By providing the possibility to better characterize the cellular diversity in their microenvironment, RS could revolutionize current diagnostic and therapeutic approaches, enabling early identification of CSCs and facilitating the development of personalized treatment strategies.
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Affiliation(s)
- Francesca Pagliari
- Division of Biomedical Physics in Radiation Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Luca Tirinato
- Department of Medical and Surgical Sciences, University Magna Graecia, 88100 Catanzaro, Italy
| | - Enzo Di Fabrizio
- PolitoBIOMed Lab DISAT Department, Polytechnic University of Turin, 10129 Turin, Italy
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4
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Nussinov R, Yavuz BR, Jang H. Tumors and their microenvironments: Learning from pediatric brain pathologies. Biochim Biophys Acta Rev Cancer 2025; 1880:189328. [PMID: 40254040 DOI: 10.1016/j.bbcan.2025.189328] [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: 12/12/2024] [Revised: 04/15/2025] [Accepted: 04/16/2025] [Indexed: 04/22/2025]
Abstract
Early clues to tumors and their microenvironments come from embryonic development. Here we review the literature and consider whether the embryonic brain and its pathologies can serve as a better model. Among embryonic organs, the brain is the most heterogenous and complex, with multiple lineages leading to wide spectrum of cell states and types. Its dysregulation promotes neurodevelopmental brain pathologies and pediatric tumors. Embryonic brain pathologies point to the crucial importance of spatial heterogeneity over time, akin to the tumor microenvironment. Tumors dedifferentiate through genetic mutations and epigenetic modulations; embryonic brains differentiate through epigenetic modulations. Our innovative review proposes learning developmental brain pathologies to target tumor evolution-and vice versa. We describe ways through which tumor pharmacology can learn from embryonic brains and their pathologies, and how learning tumor, and its microenvironment, can benefit targeting neurodevelopmental pathologies. Examples include pediatric low-grade versus high-grade brain tumors as in rhabdomyosarcomas and gliomas.
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Affiliation(s)
- Ruth Nussinov
- Computational Structural Biology Section, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Cancer Innovation Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
| | - Bengi Ruken Yavuz
- Cancer Innovation Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702, USA
| | - Hyunbum Jang
- Computational Structural Biology Section, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; Cancer Innovation Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702, USA
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5
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Guillorit H, Relier S, Zagiel B, Di Giorgio A, Planque C, Felipe B, Hérault H, Bansard L, Bouclier C, Chabi B, Casas F, Clara O, Bonafos B, Mialhe X, Cazevieille C, Hideg S, Choquet A, Bastide A, Pannequin J, Duca M, Macari F, David A. Streptomycin targets tumor-initiating cells by disrupting oxidative phosphorylation. Cell Chem Biol 2025; 32:570-585.e7. [PMID: 40209702 DOI: 10.1016/j.chembiol.2025.03.008] [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: 11/28/2023] [Revised: 02/12/2025] [Accepted: 03/19/2025] [Indexed: 04/12/2025]
Abstract
Tumor initiating cells (TICs) are the roots of current shortcomings in advanced and metastatic cancer treatment. Endowed with self-renewal and multi-lineage differentiation capacity, TICs can disseminate and seed metastasis in distant organ. Our work identified streptomycin (SM), a potent bactericidal antibiotic, as a molecule capable of specifically targeting non-adherent TIC from colon and breast cancer cell lines. SM induces iron-dependent, reactive oxygen species (ROS)-mediated cell death, which is mechanistically distinct from RSL3-induced ferroptosis. SM-induced cell death is associated with profound alterations in mitochondrial morphology. This effect results from COX1 inhibition, which disrupts the regulation of the cytochrome c oxidase complex and triggers mitochondrial ROS production. SM's aldehyde group is essential, as its reduction into dihydrostreptomycin (DSM) abolishes its activity. These findings reveal a mechanism of action for streptomycin, shedding light on TIC metabolism and resistance, with potential implications for advanced cancer treatment.
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Affiliation(s)
- Hélène Guillorit
- Institut de Génomique Fonctionnelle, Université Montpellier, CNRS, INSERM, Montpellier, France
| | - Sébastien Relier
- Institut de Génomique Fonctionnelle, Université Montpellier, CNRS, INSERM, Montpellier, France
| | - Benjamin Zagiel
- Université Côte d'Azur, CNRS, Institute of Chemistry of Nice (ICN), Nice, France
| | - Audrey Di Giorgio
- Université Côte d'Azur, CNRS, Institute of Chemistry of Nice (ICN), Nice, France
| | - Chris Planque
- Institut de Génomique Fonctionnelle, Université Montpellier, CNRS, INSERM, Montpellier, France; IRCM, Université de Montpellier, INSERM, Montpellier, France
| | - Bastien Felipe
- Institut de Génomique Fonctionnelle, Université Montpellier, CNRS, INSERM, Montpellier, France
| | - Hélène Hérault
- Institut de Génomique Fonctionnelle, Université Montpellier, CNRS, INSERM, Montpellier, France; IRCM, Université de Montpellier, INSERM, Montpellier, France
| | - Lucile Bansard
- Institut de Génomique Fonctionnelle, Université Montpellier, CNRS, INSERM, Montpellier, France
| | - Céline Bouclier
- Institut de Génomique Fonctionnelle, Université Montpellier, CNRS, INSERM, Montpellier, France
| | - Béatrice Chabi
- DMEM, Université de Montpellier, INRAE, Montpellier, France
| | - François Casas
- DMEM, Université de Montpellier, INRAE, Montpellier, France
| | - Ornella Clara
- Institut de Génomique Fonctionnelle, Université Montpellier, CNRS, INSERM, Montpellier, France
| | | | - Xavier Mialhe
- Institut de Génomique Fonctionnelle, Université Montpellier, CNRS, INSERM, Montpellier, France
| | - Chantal Cazevieille
- Institut des Neurosciences de Montpellier (INM), Université de Montpellier, Montpellier, France
| | - Szimonetta Hideg
- Institut de Génomique Fonctionnelle, Université Montpellier, CNRS, INSERM, Montpellier, France
| | - Armelle Choquet
- Institut de Génomique Fonctionnelle, Université Montpellier, CNRS, INSERM, Montpellier, France; IRCM, Université de Montpellier, INSERM, Montpellier, France
| | - Amandine Bastide
- Institut de Génomique Fonctionnelle, Université Montpellier, CNRS, INSERM, Montpellier, France
| | - Julie Pannequin
- Institut de Génomique Fonctionnelle, Université Montpellier, CNRS, INSERM, Montpellier, France
| | - Maria Duca
- Université Côte d'Azur, CNRS, Institute of Chemistry of Nice (ICN), Nice, France
| | - Françoise Macari
- Institut de Génomique Fonctionnelle, Université Montpellier, CNRS, INSERM, Montpellier, France; IRCM, Université de Montpellier, INSERM, Montpellier, France.
| | - Alexandre David
- Institut de Génomique Fonctionnelle, Université Montpellier, CNRS, INSERM, Montpellier, France; IRMB-PPC, Université de Montpellier, INSERM, CHU Montpellier, CNRS, Montpellier, France; IRCM, Université de Montpellier, INSERM, Montpellier, France.
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6
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Haddadin L, Sun X. Stem Cells in Cancer: From Mechanisms to Therapeutic Strategies. Cells 2025; 14:538. [PMID: 40214491 PMCID: PMC11988674 DOI: 10.3390/cells14070538] [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: 03/02/2025] [Revised: 03/23/2025] [Accepted: 04/01/2025] [Indexed: 04/14/2025] Open
Abstract
Stem cells have emerged as a pivotal area of research in the field of oncology, offering new insights into the mechanisms of cancer initiation, progression, and resistance to therapy. This review provides a comprehensive overview of the role of stem cells in cancer, focusing on cancer stem cells (CSCs), their characteristics, and their implications for cancer therapy. We discuss the origin and identification of CSCs, their role in tumorigenesis, metastasis, and drug resistance, and the potential therapeutic strategies targeting CSCs. Additionally, we explore the use of normal stem cells in cancer therapy, focusing on their role in tissue regeneration and their use as delivery vehicles for anticancer agents. Finally, we highlight the challenges and future directions in stem cell research in cancer.
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Affiliation(s)
| | - Xueqin Sun
- Cancer Genome and Epigenetics Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
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7
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Choi J, Kim S, Lee S, Park J. The depth of tumor hierarchy and its impact on hypertumor susceptibility. Sci Rep 2025; 15:11464. [PMID: 40181035 PMCID: PMC11968861 DOI: 10.1038/s41598-025-94852-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 03/14/2025] [Indexed: 04/05/2025] Open
Abstract
Cancer cells, despite their shared origin, could be heterogeneous with respect to their stemness, plasticity, self-renewal, and oncogenicity. Recent findings indicate that a small proportion of the cancer cells oligopolize the capacity to produce diverse cancer subtypes and metastasize to other sites. Analogous to the apical hierarchy observed in adult stem cells, such versatile cancer cells were termed cancer stem cells. Meanwhile, hypertumors that exploit the cooperation of other cancer cells may disrupt the integrity of the tumor, prompting tumor regression. The biology of cancer stem cells and hypertumors has substantial clinical potential, but no study up to date has investigated the effect of cancer hierarchy on hypertumor progression. In this study, we developed biologically relevant models that elucidate the dynamics of hypertumor progression under different hierarchical structures. Our models align with previously observed data from human breast cancer subpopulations capable of state transitions. We tested and compared the progression dynamics of cancer clusters with different characteristics. Considering the trade-off between proliferation and mutation risk, our computational results suggest that existence of the cancer stem cells with high self-renewal and replication could be the prerequisite for attaining larger cancer size. In contrast, if a small cancer size is sufficient to induce lethality, a tumor composed of homogeneous cells would take less time to reach such a threshold size. Consequently, the hierarchical structure of cancer that reaches a lethal size may vary across species, representing a relevant mechanism of Peto's paradox. The formulations presented in this study link the less attended aspects of cancer which would provide integrative insights for therapeutic strategies.
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Affiliation(s)
- Jibeom Choi
- Department of Applied Mathematics, College of Applied Sciences, Kyung Hee University, Yongin, 17104, Republic of Korea.
- School of Computational Sciences, Korea Institute for Advanced Study, Seoul, 02455, Republic of Korea.
| | - Suhyeon Kim
- Department of Applied Mathematics, College of Applied Sciences, Kyung Hee University, Yongin, 17104, Republic of Korea
| | - Sunmi Lee
- Department of Applied Mathematics, College of Applied Sciences, Kyung Hee University, Yongin, 17104, Republic of Korea
| | - Junpyo Park
- Department of Applied Mathematics, College of Applied Sciences, Kyung Hee University, Yongin, 17104, Republic of Korea.
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8
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Richter KM, Wrage M, Krekeler C, De Oliveira T, Conradi LC, Menck K, Bleckmann A. Model systems to study tumor-microbiome interactions in early-onset colorectal cancer. EMBO Mol Med 2025; 17:395-413. [PMID: 39948421 PMCID: PMC11903813 DOI: 10.1038/s44321-025-00198-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 01/13/2025] [Accepted: 01/24/2025] [Indexed: 03/14/2025] Open
Abstract
Colorectal cancer (CRC) is a major health problem, with an alarming increase of early-onset CRC (EO-CRC) cases among individuals under 50 years of age. This trend shows the urgent need for understanding the underlying mechanisms leading to EO-CRC development and progression. There is significant evidence that the gut microbiome acts as a key player in CRC by triggering molecular changes in the colon epithelium, leading to tumorigenesis. However, a comprehensive collection and comparison of methods to study such tumor-microbiome interactions in the context of EO-CRC is sparse. This review provides an overview of the available in vivo, ex vivo as well as in vitro approaches to model EO-CRC and assess the effect of gut microbes on tumor development and growth. By comparing the advantages and limitations of each model system, it highlights that, while no single model is perfect, each is suitable for studying specific aspects of microbiome-induced tumorigenesis. Taken together, multifaceted approaches can simulate the human body's complexity, aiding in the development of effective treatment and prevention strategies for EO-CRC.
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Affiliation(s)
- Katharina M Richter
- Department of Medicine A, University of Muenster, 48149, Muenster, Germany
- West German Cancer Center, University Hospital Muenster, 48149, Muenster, Germany
| | - Marius Wrage
- Department of Medicine A, University of Muenster, 48149, Muenster, Germany
- West German Cancer Center, University Hospital Muenster, 48149, Muenster, Germany
| | - Carolin Krekeler
- Department of Medicine A, University of Muenster, 48149, Muenster, Germany
- West German Cancer Center, University Hospital Muenster, 48149, Muenster, Germany
| | - Tiago De Oliveira
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, 37075, Goettingen, Germany
| | - Lena-Christin Conradi
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, 37075, Goettingen, Germany
| | - Kerstin Menck
- Department of Medicine A, University of Muenster, 48149, Muenster, Germany
- West German Cancer Center, University Hospital Muenster, 48149, Muenster, Germany
| | - Annalen Bleckmann
- Department of Medicine A, University of Muenster, 48149, Muenster, Germany.
- West German Cancer Center, University Hospital Muenster, 48149, Muenster, Germany.
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9
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Zhang N, Qiu X, Chen X, Du C, Dong J, Li X, Chen B, Zhang L, Zhang Y. Survival expectations in melanoma patients: a molecular prognostic model associated with aging. Discov Oncol 2025; 16:253. [PMID: 40019657 PMCID: PMC11874052 DOI: 10.1007/s12672-025-01971-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 02/11/2025] [Indexed: 03/01/2025] Open
Abstract
BACKGROUND Aging and long non-coding RNAs (lncRNAs) are research hotspots in melanoma. However, no study has so far explored the relationship between melanoma prognosis and aging-related lncRNAs (ARLs). METHODS The Cancer Genome Atlas database, the GTEx database, and the HAGR database were used in this study in a combined manner. Univariate and multivariate cox regression analyses were used to screen out lncRNA signatures associated with overall survival (OS) in the primary dataset. The risk scoring model was analyzed by risk stratification and tested internally. The protein expression levels of possible target genes of ARLs were verified by immunohistochemistry analysis in HPA database. Finally, gene enrichment analysis was performed. RESULTS In the primary dataset, five OS-related lncRNA signatures (AC011481.1, USP30-AS1, EBLN3P, LINC01527, HLA-DQB1-AS1) were screened out. The survival curve showed that the high-risk group had a worse prognosis than the low-risk group. The immunohistochemical analysis revealed that reduced expression of Epidermal Growth Factor Receptor (EGFR), along with increased expression of Activating Transcription Factor 2 (ATF2) and DNA Polymerase Delta 1 (POLD1), was linked to a worse prognosis. Finally, enrichment analysis revealed that OS-related DELs were significantly enriched in the regulation of reactive oxygen metabolism, etc. The ARGs were significantly activated in the SKCM tissues. The regulation of aging in melanoma cells may be realized through ferroptosis, immunity, and autophagy and so on. CONCLUSION The ARL signature obtained in this study had better prognostic ability than individual clinical features.
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Affiliation(s)
- Nenghua Zhang
- Clinical Laboratory, Jiaxing Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Jiaxing, 314033, China
| | - Xinyi Qiu
- The First School of Clinical Medicine, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Xingying Chen
- Clinical Laboratory, Jiaxing Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Jiaxing, 314033, China
| | - Cheng Du
- Ophthalmology Department, Jiaxing Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Jiaxing, 314033, China
| | - Jingyi Dong
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Xiaohong Li
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Bing Chen
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Lin Zhang
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
| | - Yuyan Zhang
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
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10
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Zheng F, Zhang S, Chang AE, Moon JJ, Wicha MS, Wang SX, Chen J, Liu J, Cheng F, Li Q. Breaking Immunosuppression to Enhance Cancer Stem Cell-Targeted Immunotherapy. Int J Biol Sci 2025; 21:1819-1836. [PMID: 39990669 PMCID: PMC11844285 DOI: 10.7150/ijbs.101025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 12/03/2024] [Indexed: 02/25/2025] Open
Abstract
Cancer stem cell (CSC)-targeted immunotherapy has emerged as a novel strategy in cancer treatment in the past decade. However, its efficacy is significantly limited due to the existence of host immune suppressive activity. Specifically, programmed cell death ligand-1 (PD-L1) is overexpressed in CSCs, and PD-L1 overexpressed CSCs create immunosuppressive milieu via interacting with various immune cells in tumor microenvironments (TME). Hence, novel immunotherapeutic strategies targeting CSCs with concurrent immunosuppression interruption will be promising in enhancing anti-CSC effects. These include dendritic cell (DC) and nanodisc (ND)-based vaccines to present CSC antigens in the forms of CSC lysate, CSC-marker proteins, and CSC-derived peptides to induce anti-CSC immunity. In addition, CSC-directed bispecific antibodies (BiAbs) and antibody drug conjugates (ADCs) have been developed to target CSCs effectively. Furthermore, chimeric antigen receptor (CAR)-T cell therapy and natural killer (NK) cell-based therapy targeting CSCs have achieved progress in both solid and hematologic tumors, and inhibition of CSC associated signaling pathways has proven successful. In this review, we aimed to outline the roles and regulatory mechanisms of PD-L1 in the properties of CSCs; the crosstalk between CSCs and immunosuppressive cells in TME, and recent progress and future promises of immunosuppression blockage to enhance CSC-targeted immunotherapy.
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Affiliation(s)
- Fang Zheng
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Shan Zhang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Alfred E. Chang
- Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - James J. Moon
- Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - Max S. Wicha
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA
| | | | - Junhui Chen
- Peking University Shenzhen Hospital, Shenzhen, China
| | - Jixian Liu
- Peking University Shenzhen Hospital, Shenzhen, China
| | - Fanjun Cheng
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Qiao Li
- Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA
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11
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Chen S, Huang C, Li K, Cheng M, Zhang C, Xiong J, Tian G, Zhou R, Ling R, Wang X, Xiong G, Zhang Z, Ma J, Zhu Y, Zhou B, Peng L, Peng Z, Li H, Chen D. Tumor-initiating cells escape tumor immunity via CCL8 from tumor-associated macrophages in mice. J Clin Invest 2025; 135:e180893. [PMID: 39774471 PMCID: PMC11870738 DOI: 10.1172/jci180893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 01/03/2025] [Indexed: 01/11/2025] Open
Abstract
Tumor-initiating cells (TICs) play a key role in cancer progression and immune escape. However, how TICs evade immune elimination remains poorly characterized. Combining single-cell RNA-Seq (scRNA-Seq), dual-recombinase-based lineage tracing, and other approaches, we identified a WNT-activated subpopulation of malignant cells that act as TICs in vivo. We found intensive reciprocal interactions between TICs and immune-regulatory tumor-associated macrophages (Reg-TAMs) via growth arrest-specific 6/AXL receptor tyrosine kinase/MER proto-oncogene, tyrosine kinase (GAS6/AXL/MERTK) signaling pathways, which facilitated the immune escape of TICs. In this study, we used chemical inhibitors and Axl/Mertk conditional double-KO (cDKO) mice to demonstrate that inhibiting the interaction between TIC-derived GAS6 and AXL/MERTK in Reg-TAMs reactivated antitumor immune responses. We identified CCL8 as a critical mediator of the GAS6/AXL/MERTK pathway, primarily by inhibiting Treg infiltration into the tumor. Furthermore, the AXL/MERTK signaling blockade sensitized tumor cells to anti-programmed cell death 1 (anti-PD-1) treatment. Thus, we elucidated a detailed mechanism by which TICs evade tumor immunity, providing insights into strategies to eradicate TICs that escape conventional immunotherapy.
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Affiliation(s)
- Shuang Chen
- Department of Otorhinolaryngology, Department of Medical Oncology, Department of Pancreato-Biliary Surgery, Department of Radiation Oncology, Cancer Center, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University (FAHSYSU), Guangzhou, China
| | - Chensong Huang
- Department of Otorhinolaryngology, Department of Medical Oncology, Department of Pancreato-Biliary Surgery, Department of Radiation Oncology, Cancer Center, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University (FAHSYSU), Guangzhou, China
| | - Kang Li
- Department of Otorhinolaryngology, Department of Medical Oncology, Department of Pancreato-Biliary Surgery, Department of Radiation Oncology, Cancer Center, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University (FAHSYSU), Guangzhou, China
| | - Maosheng Cheng
- Department of Otorhinolaryngology, Department of Medical Oncology, Department of Pancreato-Biliary Surgery, Department of Radiation Oncology, Cancer Center, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University (FAHSYSU), Guangzhou, China
| | - Caihua Zhang
- Department of Otorhinolaryngology, Department of Medical Oncology, Department of Pancreato-Biliary Surgery, Department of Radiation Oncology, Cancer Center, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University (FAHSYSU), Guangzhou, China
| | - Jianqi Xiong
- Department of Otorhinolaryngology, Department of Medical Oncology, Department of Pancreato-Biliary Surgery, Department of Radiation Oncology, Cancer Center, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University (FAHSYSU), Guangzhou, China
| | - Guoli Tian
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Ruoxing Zhou
- Department of Otorhinolaryngology, Department of Medical Oncology, Department of Pancreato-Biliary Surgery, Department of Radiation Oncology, Cancer Center, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University (FAHSYSU), Guangzhou, China
| | - Rongsong Ling
- Department of Otorhinolaryngology, Department of Medical Oncology, Department of Pancreato-Biliary Surgery, Department of Radiation Oncology, Cancer Center, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University (FAHSYSU), Guangzhou, China
| | - Xiaochen Wang
- Department of Otorhinolaryngology, Department of Medical Oncology, Department of Pancreato-Biliary Surgery, Department of Radiation Oncology, Cancer Center, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University (FAHSYSU), Guangzhou, China
| | - Gan Xiong
- Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhihui Zhang
- Department of Otorhinolaryngology, Department of Medical Oncology, Department of Pancreato-Biliary Surgery, Department of Radiation Oncology, Cancer Center, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University (FAHSYSU), Guangzhou, China
| | - Jieyi Ma
- Department of Otorhinolaryngology, Department of Medical Oncology, Department of Pancreato-Biliary Surgery, Department of Radiation Oncology, Cancer Center, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University (FAHSYSU), Guangzhou, China
| | - Yan Zhu
- Department of Otorhinolaryngology, Department of Medical Oncology, Department of Pancreato-Biliary Surgery, Department of Radiation Oncology, Cancer Center, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University (FAHSYSU), Guangzhou, China
| | - Bin Zhou
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Liang Peng
- Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Zhenwei Peng
- Department of Otorhinolaryngology, Department of Medical Oncology, Department of Pancreato-Biliary Surgery, Department of Radiation Oncology, Cancer Center, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University (FAHSYSU), Guangzhou, China
| | - Heping Li
- Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Demeng Chen
- Department of Otorhinolaryngology, Department of Medical Oncology, Department of Pancreato-Biliary Surgery, Department of Radiation Oncology, Cancer Center, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University (FAHSYSU), Guangzhou, China
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
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12
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Kudelka MR, Lavin Y, Sun S, Fuchs E. Molecular and cellular dynamics of squamous cell carcinomas across tissues. Genes Dev 2025; 39:18-35. [PMID: 39455281 PMCID: PMC11789493 DOI: 10.1101/gad.351990.124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2024]
Abstract
Squamous cell carcinomas (SCCs), arising from the skin, head and neck, lungs, esophagus, and cervix, are collectively among the most common cancers and a frequent cause of cancer morbidity and mortality. Despite distinct stratified epithelial tissues of origin, converging evidence points toward shared biologic pathways across SCCs. With recent breakthroughs in molecular technologies have come novel SCC treatment paradigms, including immunotherapies and targeted therapy. This review compares commonalities and differences across SCCs from different anatomical sites, including risk factors and genetics, as well as cellular and molecular programs driving tumorigenesis. We review landmark discoveries of the "cancer stem cells" (CSCs) that initiate and propagate SCCs and their gene and translational regulation programs. This has led to an appreciation that interactions between CSCs and the immune system play key roles in invasion and therapeutic resistance. Here, we review the unifying principles of SCCs that have emerged from these exciting advances in our understanding of these epithelial cancers.
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Affiliation(s)
- Matthew R Kudelka
- Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New York 10065, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Yonit Lavin
- Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New York 10065, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Siman Sun
- Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New York 10065, USA
| | - Elaine Fuchs
- Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New York 10065, USA;
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13
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Zhang X, Huang Y, Yang Y, Wang QE, Li L. Advancements in prospective single-cell lineage barcoding and their applications in research. Genome Res 2024; 34:2147-2162. [PMID: 39572229 PMCID: PMC11694748 DOI: 10.1101/gr.278944.124] [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: 01/05/2024] [Accepted: 10/03/2024] [Indexed: 12/25/2024]
Abstract
Single-cell lineage tracing (scLT) has emerged as a powerful tool, providing unparalleled resolution to investigate cellular dynamics, fate determination, and the underlying molecular mechanisms. This review thoroughly examines the latest prospective lineage DNA barcode tracing technologies. It further highlights pivotal studies that leverage single-cell lentiviral integration barcoding technology to unravel the dynamic nature of cell lineages in both developmental biology and cancer research. Additionally, the review navigates through critical considerations for successful experimental design in lineage tracing and addresses challenges inherent in this field, including technical limitations, complexities in data analysis, and the imperative for standardization. It also outlines current gaps in knowledge and suggests future research directions, contributing to the ongoing advancement of scLT studies.
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Affiliation(s)
- Xiaoli Zhang
- College of Nursing, University of South Florida, Tampa, Florida 33620, USA;
| | - Yirui Huang
- College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA
| | - Yajing Yang
- Department of Radiation Oncology, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA
| | - Qi-En Wang
- Department of Radiation Oncology, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA
| | - Lang Li
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA
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14
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Sonnentag SJ, Ibrahim NSM, Orian-Rousseau V. CD44: a stemness driver, regulator, and marker-all in one? Stem Cells 2024; 42:1031-1039. [PMID: 39364735 DOI: 10.1093/stmcls/sxae060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 08/23/2024] [Indexed: 10/05/2024]
Abstract
Although the concept of cancer stem cells is still controversial, previous studies have shown that blood cancers, as well as specific types of solid cancers such as colorectal cancer, rely on stem cells during the onset of tumor growth and further tumor development. Moreover, resistance to therapeutic treatment in leukemias such as acute myeloid leukemia and in colorectal cancer can be attributed to a small population of cells with stemness properties known as minimal residual disease. In this review, we look back on the discovery of cancer stem cells and the contribution of the findings in blood cancer to a parallel discovery in solid cancers. We focus on CD44 as a stem cell marker, both in blood cancers and in several types of solid cancers, particularly of the gastrointestinal tract. This review highlights newly discovered molecular mechanisms of action of CD44 which indicate that CD44 has indeed a function in stemness, stem cell maintenance, and drug resistance. We attempt here to make the link between the functions of CD44 isoforms in stemness and their involvement in specific steps of tumor growth and metastasis.
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Affiliation(s)
- Steffen J Sonnentag
- Karlsruhe Institute of Technology, Institute of Biological and Chemical Systems-Functional Molecular Systems, Kaiserstraße 12, 76131 Karlsruhe, Germany
| | - Nagwa S M Ibrahim
- Karlsruhe Institute of Technology, Institute of Biological and Chemical Systems-Functional Molecular Systems, Kaiserstraße 12, 76131 Karlsruhe, Germany
| | - Veronique Orian-Rousseau
- Karlsruhe Institute of Technology, Institute of Biological and Chemical Systems-Functional Molecular Systems, Kaiserstraße 12, 76131 Karlsruhe, Germany
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15
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Nease LA, Church KP, Delclaux I, Murakami S, Astorkia M, Zerhouni M, Cascio G, Hughes RO, Aguirre KN, Zumbo P, Dow LE, Jaffrey S, Betel D, Piskounova E. Selenocysteine tRNA methylation promotes oxidative stress resistance in melanoma metastasis. NATURE CANCER 2024; 5:1868-1884. [PMID: 39438623 DOI: 10.1038/s43018-024-00844-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 09/25/2024] [Indexed: 10/25/2024]
Abstract
Selenocysteine-containing proteins play a central role in redox homeostasis. Their translation is a highly regulated process and is dependent on two tRNASec isodecoders differing by a single 2'-O-ribose methylation called Um34. Here we characterized FTSJ1 as the Um34 methyltransferase and show that its activity is required for efficient selenocysteine insertion at the UGA stop codon during translation. Specifically, loss of Um34 leads to ribosomal stalling and decreased UGA recoding. FTSJ1-deficient cells are more sensitive to oxidative stress and show decreased metastatic colonization in xenograft models of melanoma metastasis. We found that FTSJ1 mediates efficient translation of selenoproteins essential for the cellular antioxidant response. Our findings uncover a role for tRNASec Um34 modification in oxidative stress resistance and highlight FTSJ1 as a potential therapeutic target specific for metastatic disease.
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Affiliation(s)
- Leona A Nease
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
| | - Kellsey P Church
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Ines Delclaux
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Shino Murakami
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
| | - Maider Astorkia
- Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA
| | - Marwa Zerhouni
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Graciela Cascio
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Riley O Hughes
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
| | - Kelsey N Aguirre
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Paul Zumbo
- Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA
| | - Lukas E Dow
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
- Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA
- Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Samie Jaffrey
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
| | - Doron Betel
- Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA
- Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA
- Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Elena Piskounova
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
- Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA.
- Department of Dermatology, Weill Cornell Medicine, New York, NY, USA.
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16
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Xu A, Liu J, Tong L, Shen T, Xing S, Xia Y, Zhang B, Wu Z, Yuan W, Yu A, Kan Z, Yang W, Zhang C, Zhang C. Machine Learning Reveals Aneuploidy Characteristics in Cancers: The Impact of BEX4. FRONT BIOSCI-LANDMRK 2024; 29:407. [PMID: 39735979 DOI: 10.31083/j.fbl2912407] [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: 06/15/2024] [Revised: 08/23/2024] [Accepted: 08/30/2024] [Indexed: 12/31/2024]
Abstract
BACKGROUND Aneuploidy is crucial yet under-explored in cancer pathogenesis. Specifically, the involvement of brain expressed X-linked gene 4 (BEX4) in microtubule formation has been identified as a potential aneuploidy mechanism. Nevertheless, BEX4's comprehensive impact on aneuploidy incidence across different cancer types remains unexplored. METHODS Patients from The Cancer Genome Atlas (TCGA) were stratified into high-score (training) and low-score (control) groups based on the aneuploidy score. Mfuzz expression pattern clustering and functional enrichment were applied to genes with BEX4 as the core to explore their regulatory mechanisms. Various machine learning techniques were employed to screen aneuploidy-associated genes, after which aneuploidy characteristic subtypes were established in cancers. Moreover, the aneuploidy characteristics across multiple cancer types were investigated by integrating the extent of tumor cell stemness acquisition and a series of immune traits. Immunohistochemistry and proliferation assay mainly verified the anti-tumor effect of different BEX4 level. RESULTS Functional clustering results showed that aneuploidy and stemness were significantly associated in kidney chromophobe (KICH) and thyroid carcinoma (THCA). And cell metabolism and cell cycle had key effects. Residual analysis indicates superior screening performance by random forest (RF). An aneuploid feature gene set with BEX4 as the core was screened to construct a Nomogram model. BEX4, calmodulin regulated spectrin associated protein 2 (CAMSAP2), and myristoylated alanine rich protein kinase C substrate (MARCKS) were identified as aneuploidy characteristic hub genes. Molecular subtypes in thymoma (THYM), thyroid carcinoma (THCA), and kidney chromophobe (KICH) showed significant differences in tumor cell stemness among different subtypes. The competitive endogenous RNA (ceRNA)-Genes network revealed that hub genes, co-regulated by hsa-miR-425-5p, hsa-miR-200c-3p, and others, regulate microtubules, centrosomes, and microtubule cytoskeleton. Furthermore, elevated BEX4 emerged as a significant protective factor in Pancreatic adenocarcinoma (PAAD), KICH, kidney renal papillary cell carcinoma (KIRP), and kidney renal clear cell carcinoma (KIRC). CONCLUSIONS BEX4, CAMSAP2, and MARCKS specifically express in microtubules, centrioles, and cytoskeletons, influencing tumor chromosome division and inducing aneuploidy. Additionally, the relationship between the acquisition of tumor cell stemness and the severity of aneuploidy varies significantly across tumor types, displaying positive and negative correlations.
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Affiliation(s)
- Aizhong Xu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China
- Department of General Surgery, Anqing Municipal Hospital, 246000 Anqing, Anhui, China
| | - Jianjun Liu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China
| | - Li Tong
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China
| | - Tingting Shen
- Clinical Pathology Center, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China
- Clinical Pathology Center, Anhui Public Health Clinical Center, 230011 Hefei, Anhui, China
| | - Songlin Xing
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China
- School of Basic Medical Sciences, Anhui Medical University, 230032 Hefei, Anhui, China
| | - Yujie Xia
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China
| | - Bosen Zhang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China
| | - Zihao Wu
- Clinical Pathology Center, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China
- Clinical Pathology Center, Anhui Public Health Clinical Center, 230011 Hefei, Anhui, China
| | - Wenkang Yuan
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China
| | - Anhai Yu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China
| | - Zijie Kan
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China
| | - Wenqi Yang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China
| | - Chao Zhang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China
| | - Chong Zhang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China
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17
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Bushnell GG, Sharma D, Wilmot HC, Zheng M, Fashina TD, Hutchens CM, Osipov S, Burness M, Wicha MS. Natural Killer Cell Regulation of Breast Cancer Stem Cells Mediates Metastatic Dormancy. Cancer Res 2024; 84:3337-3353. [PMID: 39106452 PMCID: PMC11474167 DOI: 10.1158/0008-5472.can-24-0030] [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: 01/04/2024] [Revised: 06/04/2024] [Accepted: 07/31/2024] [Indexed: 08/09/2024]
Abstract
Patients with breast cancer with estrogen receptor-positive tumors face a constant risk of disease recurrence for the remainder of their lives. Dormant tumor cells residing in tissues such as the bone marrow may generate clinically significant metastases many years after initial diagnosis. Previous studies suggest that dormant cancer cells display "stem-like" properties (cancer stem cell, CSC), which may be regulated by the immune system. To elucidate the role of the immune system in controlling dormancy and its escape, we studied dormancy in immunocompetent, syngeneic mouse breast cancer models. Three mouse breast cancer cell lines, PyMT, Met1, and D2.0R, contained CSCs that displayed short- and long-term metastatic dormancy in vivo, which was dependent on the host immune system. Each model was regulated by different components of the immune system. Natural killer (NK) cells were key for the metastatic dormancy phenotype in D2.0R cells. Quiescent D2.0R CSCs were resistant to NK cell cytotoxicity, whereas proliferative CSCs were sensitive. Resistance to NK cell cytotoxicity was mediated, in part, by the expression of BACH1 and SOX2 transcription factors. Expression of STING and STING targets was decreased in quiescent CSCs, and the STING agonist MSA-2 enhanced NK cell killing. Collectively, these findings demonstrate the role of immune regulation of breast tumor dormancy and highlight the importance of utilizing immunocompetent models to study this phenomenon. Significance: The immune system controls disseminated breast cancer cells during disease latency, highlighting the need to utilize immunocompetent models to identify strategies for targeting dormant cancer cells and reducing metastatic recurrence. See related commentary by Cackowski and Korkaya, p. 3319.
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Affiliation(s)
- Grace G. Bushnell
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
| | - Deeksha Sharma
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
| | - Henry C. Wilmot
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
| | - Michelle Zheng
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
| | | | - Chloe M. Hutchens
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
| | - Samuel Osipov
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
| | - Monika Burness
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
| | - Max S. Wicha
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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18
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Parikh R, Parikh S, Berzin D, Vaknine H, Ovadia S, Likonen D, Greenberger S, Scope A, Elgavish S, Nevo Y, Plaschkes I, Nizri E, Kobiler O, Maliah A, Zaremba L, Mohan V, Sagi I, Ashery-Padan R, Carmi Y, Luxenburg C, Hoheisel JD, Khaled M, Levesque MP, Levy C. Recycled melanoma-secreted melanosomes regulate tumor-associated macrophage diversification. EMBO J 2024; 43:3553-3586. [PMID: 38719996 PMCID: PMC11377571 DOI: 10.1038/s44318-024-00103-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 02/06/2024] [Accepted: 03/26/2024] [Indexed: 09/07/2024] Open
Abstract
Extracellular vesicles (EVs) are important mediators of communication between cells. Here, we reveal a new mode of intercellular communication by melanosomes, large EVs secreted by melanocytes for melanin transport. Unlike small EVs, which are disintegrated within the receiver cell, melanosomes stay intact within them, gain a unique protein signature, and can then be further transferred to another cell as "second-hand" EVs. We show that melanoma-secreted melanosomes passaged through epidermal keratinocytes or dermal fibroblasts can be further engulfed by resident macrophages. This process leads to macrophage polarization into pro-tumor or pro-immune cell infiltration phenotypes. Melanosomes that are transferred through fibroblasts can carry AKT1, which induces VEGF secretion from macrophages in an mTOR-dependent manner, promoting angiogenesis and metastasis in vivo. In melanoma patients, macrophages that are co-localized with AKT1 are correlated with disease aggressiveness, and immunotherapy non-responders are enriched in macrophages containing melanosome markers. Our findings suggest that interactions mediated by second-hand extracellular vesicles contribute to the formation of the metastatic niche, and that blocking the melanosome cues of macrophage diversification could be helpful in halting melanoma progression.
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Affiliation(s)
- Roma Parikh
- Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel
| | - Shivang Parikh
- Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel
- The Ragon Institute of Mass General, Massachusetts Institute of Technology (MIT), and Harvard, MA 02139, Cambridge, USA
| | - Daniella Berzin
- Institute of Pathology, Sheba Medical Center, Tel Hashomer, 52621, Israel
| | - Hananya Vaknine
- Institute of Pathology, E. Wolfson Medical Center, Holon, 58100, Israel
| | - Shai Ovadia
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neurosciences, Tel Aviv University, Tel Aviv, 69978, Israel
| | - Daniela Likonen
- Institute of Pathology, Sheba Medical Center, Tel Hashomer, 52621, Israel
| | | | - Alon Scope
- The Kittner Skin Cancer Screening and Research Institute, Sheba Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Sharona Elgavish
- Info-CORE, Bioinformatics Unit of the I-CORE at the Hebrew University of Jerusalem and Hadassah Medical Center, Jerusalem, 91120, Israel
| | - Yuval Nevo
- Info-CORE, Bioinformatics Unit of the I-CORE at the Hebrew University of Jerusalem and Hadassah Medical Center, Jerusalem, 91120, Israel
| | - Inbar Plaschkes
- Info-CORE, Bioinformatics Unit of the I-CORE at the Hebrew University of Jerusalem and Hadassah Medical Center, Jerusalem, 91120, Israel
| | - Eran Nizri
- Department of Dermatology, Tel Aviv Sourasky (Ichilov) Medical Center, Tel Aviv, 6423906, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel
| | - Oren Kobiler
- Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv Universitygrid.12136.37, Tel Aviv, Israel
| | - Avishai Maliah
- Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel
| | - Laureen Zaremba
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Vishnu Mohan
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, 7610001, Israel
| | - Irit Sagi
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, 7610001, Israel
| | - Ruth Ashery-Padan
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neurosciences, Tel Aviv University, Tel Aviv, 69978, Israel
| | - Yaron Carmi
- Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel
| | - Chen Luxenburg
- Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel
| | - Jörg D Hoheisel
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Mehdi Khaled
- INSERM 1279, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Mitchell P Levesque
- Department of Dermatology, University of Zurich, University Hospital Zurich, Wagistrasse 18, CH-8952, Schlieren, Switzerland
| | - Carmit Levy
- Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
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19
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Hantusch B, Kenner L, Stanulović VS, Hoogenkamp M, Brown G. Targeting Androgen, Thyroid Hormone, and Vitamin A and D Receptors to Treat Prostate Cancer. Int J Mol Sci 2024; 25:9245. [PMID: 39273194 PMCID: PMC11394715 DOI: 10.3390/ijms25179245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 08/20/2024] [Accepted: 08/23/2024] [Indexed: 09/15/2024] Open
Abstract
The nuclear hormone family of receptors regulates gene expression. The androgen receptor (AR), upon ligand binding and homodimerization, shuttles from the cytosol into the nucleus to activate gene expression. Thyroid hormone receptors (TRs), retinoic acid receptors (RARs), and the vitamin D receptor (VDR) are present in the nucleus bound to chromatin as a heterodimer with the retinoid X receptors (RXRs) and repress gene expression. Ligand binding leads to transcription activation. The hormonal ligands for these receptors play crucial roles to ensure the proper conduct of very many tissues and exert effects on prostate cancer (PCa) cells. Androgens support PCa proliferation and androgen deprivation alone or with chemotherapy is the standard therapy for PCa. RARγ activation and 3,5,3'-triiodo-L-thyronine (T3) stimulation of TRβ support the growth of PCa cells. Ligand stimulation of VDR drives growth arrest, differentiation, and apoptosis of PCa cells. Often these receptors are explored as separate avenues to find treatments for PCa and other cancers. However, there is accumulating evidence to support receptor interactions and crosstalk of regulatory events whereby a better understanding might lead to new combinatorial treatments.
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Affiliation(s)
- Brigitte Hantusch
- Department of Pathology, Department for Experimental and Laboratory Animal Pathology, Medical University of Vienna, 1010 Vienna, Austria;
- Comprehensive Cancer Center, Medical University Vienna, 1090 Vienna, Austria
| | - Lukas Kenner
- Department of Pathology, Department for Experimental and Laboratory Animal Pathology, Medical University of Vienna, 1010 Vienna, Austria;
- Comprehensive Cancer Center, Medical University Vienna, 1090 Vienna, Austria
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
- Department of Molecular Biology, Umeå University, 901 87 Umeå, Sweden
- Christian Doppler Laboratory for Applied Metabolomics, Medical University Vienna, 1090 Vienna, Austria
- Center for Biomarker Research in Medicine (CBmed), 8010 Graz, Austria
| | - Vesna S. Stanulović
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; (V.S.S.); (M.H.)
| | - Maarten Hoogenkamp
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; (V.S.S.); (M.H.)
| | - Geoffrey Brown
- School of Biomedical Sciences, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
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20
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Limonta P, Chiaramonte R, Casati L. Unveiling the Dynamic Interplay between Cancer Stem Cells and the Tumor Microenvironment in Melanoma: Implications for Novel Therapeutic Strategies. Cancers (Basel) 2024; 16:2861. [PMID: 39199632 PMCID: PMC11352669 DOI: 10.3390/cancers16162861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 08/07/2024] [Accepted: 08/13/2024] [Indexed: 09/01/2024] Open
Abstract
Cutaneous melanoma still represents a significant health burden worldwide, being responsible for the majority of skin cancer deaths. Key advances in therapeutic strategies have significantly improved patient outcomes; however, most patients experience drug resistance and tumor relapse. Cancer stem cells (CSCs) are a small subpopulation of cells in different tumors, including melanoma, endowed with distinctive capacities of self-renewal and differentiation into bulk tumor cells. Melanoma CSCs are characterized by the expression of specific biomarkers and intracellular pathways; moreover, they play a pivotal role in tumor onset, progression and drug resistance. In recent years, great efforts have been made to dissect the molecular mechanisms underlying the protumor activities of melanoma CSCs to provide the basis for novel CSC-targeted therapies. Herein, we highlight the intricate crosstalk between melanoma CSCs and bystander cells in the tumor microenvironment (TME), including immune cells, endothelial cells and cancer-associated fibroblasts (CAFs), and its role in melanoma progression. Specifically, we discuss the peculiar capacities of melanoma CSCs to escape the host immune surveillance, to recruit immunosuppressive cells and to educate immune cells toward an immunosuppressive and protumor phenotype. We also address currently investigated CSC-targeted strategies that could pave the way for new promising therapeutic approaches for melanoma care.
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Affiliation(s)
- Patrizia Limonta
- Department of Pharmacological and Biomolecular Sciences “R. Paoletti”, Università degli Studi di Milano, 20133 Milan, Italy
| | - Raffaella Chiaramonte
- Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy;
| | - Lavinia Casati
- Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy;
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21
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Atwani R, Nagare RP, Rogers A, Prasad M, Lazar V, Sandusky G, Tong Y, Pin F, Condello S. Integrin-linked kinase-frizzled 7 interaction maintains cancer stem cells to drive platinum resistance in ovarian cancer. J Exp Clin Cancer Res 2024; 43:156. [PMID: 38822429 PMCID: PMC11143768 DOI: 10.1186/s13046-024-03083-y] [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: 02/12/2024] [Accepted: 05/27/2024] [Indexed: 06/03/2024] Open
Abstract
BACKGROUND Platinum-based chemotherapy regimens are a mainstay in the management of ovarian cancer (OC), but emergence of chemoresistance poses a significant clinical challenge. The persistence of ovarian cancer stem cells (OCSCs) at the end of primary treatment contributes to disease recurrence. Here, we hypothesized that the extracellular matrix protects CSCs during chemotherapy and supports their tumorigenic functions by activating integrin-linked kinase (ILK), a key enzyme in drug resistance. METHODS TCGA datasets and OC models were investigated using an integrated proteomic and gene expression analysis and examined ILK for correlations with chemoresistance pathways and clinical outcomes. Canonical Wnt pathway components, pro-survival signaling, and stemness were examined using OC models. To investigate the role of ILK in the OCSC-phenotype, a novel pharmacological inhibitor of ILK in combination with carboplatin was utilized in vitro and in vivo OC models. RESULTS In response to increased fibronectin secretion and integrin β1 clustering, aberrant ILK activation supported the OCSC phenotype, contributing to OC spheroid proliferation and reduced response to platinum treatment. Complexes formed by ILK with the Wnt receptor frizzled 7 (Fzd7) were detected in tumors and correlated with metastatic progression. Moreover, TCGA datasets confirmed that combined expression of ILK and Fzd7 in high grade serous ovarian tumors is correlated with reduced response to chemotherapy and poor patient outcomes. Mechanistically, interaction of ILK with Fzd7 increased the response to Wnt ligands, thereby amplifying the stemness-associated Wnt/β-catenin signaling. Notably, preclinical studies showed that the novel ILK inhibitor compound 22 (cpd-22) alone disrupted ILK interaction with Fzd7 and CSC proliferation as spheroids. Furthermore, when combined with carboplatin, this disruption led to sustained AKT inhibition, apoptotic damage in OCSCs and reduced tumorigenicity in mice. CONCLUSIONS This "outside-in" signaling mechanism is potentially actionable, and combined targeting of ILK-Fzd7 may lead to new therapeutic approaches to eradicate OCSCs and improve patient outcomes.
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Affiliation(s)
- Rula Atwani
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
| | - Rohit Pravin Nagare
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
| | - Amber Rogers
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
- Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Mayuri Prasad
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
| | - Virginie Lazar
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
| | - George Sandusky
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Yan Tong
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Fabrizio Pin
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Salvatore Condello
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA.
- Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
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22
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Calhoon D, Sang L, Bezwada D, Kim N, Basu A, Hsu SC, Pimentel A, Brooks B, La K, Serrano AP, Cassidy DL, Cai L, Toffessi-Tcheuyap V, Margulis V, Cai F, Brugarolas J, Weiss RJ, DeBerardinis RJ, Birsoy K, Garcia-Bermudez J. Glycosaminoglycan-mediated lipoprotein uptake protects cancer cells from ferroptosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.13.593939. [PMID: 38765991 PMCID: PMC11101130 DOI: 10.1101/2024.05.13.593939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Lipids are essential for tumours because of their structural, energetic, and signaling roles. While many cancer cells upregulate lipid synthesis, growing evidence suggests that tumours simultaneously intensify the uptake of circulating lipids carried by lipoproteins. Which mechanisms promote the uptake of extracellular lipids, and how this pool of lipids contributes to cancer progression, are poorly understood. Here, using functional genetic screens, we find that lipoprotein uptake confers resistance to lipid peroxidation and ferroptotic cell death. Lipoprotein supplementation robustly inhibits ferroptosis across numerous cancer types. Mechanistically, cancer cells take up lipoproteins through a pathway dependent on sulfated glycosaminoglycans (GAGs) linked to cell-surface proteoglycans. Tumour GAGs are a major determinant of the uptake of both low and high density lipoproteins. Impairment of glycosaminoglycan synthesis or acute degradation of surface GAGs decreases the uptake of lipoproteins, sensitizes cells to ferroptosis and reduces tumour growth in mice. We also find that human clear cell renal cell carcinomas, a distinctively lipid-rich tumour type, display elevated levels of lipoprotein-derived antioxidants and the GAG chondroitin sulfate than non-malignant human kidney. Altogether, our work identifies lipoprotein uptake as an essential anti-ferroptotic mechanism for cancer cells to overcome lipid oxidative stress in vivo, and reveals GAG biosynthesis as an unexpected mediator of this process.
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Affiliation(s)
- Dylan Calhoon
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
- These authors contributed equally to this work
| | - Lingjie Sang
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
- These authors contributed equally to this work
| | - Divya Bezwada
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Nathaniel Kim
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Amrita Basu
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA
| | - Sheng-Chieh Hsu
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Anastasia Pimentel
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Bailey Brooks
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Konnor La
- Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA
| | - Ana Paulina Serrano
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Daniel L Cassidy
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ling Cai
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Quantitative Biomedical Research Center, Peter O’Donnell School of Public Health, University of Texas Southwestern, Dallas, TX, USA
| | - Vanina Toffessi-Tcheuyap
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Vitaly Margulis
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Feng Cai
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - James Brugarolas
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ryan J Weiss
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA
- Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, USA
| | - Ralph J. DeBerardinis
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Kivanç Birsoy
- Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA
| | - Javier Garcia-Bermudez
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
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23
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Bamodu OA, Chung CC, Pisanic TR, Wu ATH. The intricate interplay between cancer stem cells and cell-of-origin of cancer: implications for therapeutic strategies. Front Oncol 2024; 14:1404628. [PMID: 38800385 PMCID: PMC11116576 DOI: 10.3389/fonc.2024.1404628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 04/25/2024] [Indexed: 05/29/2024] Open
Abstract
Background Cancer stem cells (CSCs) have emerged as pivotal players in tumorigenesis, disease progression, and resistance to therapies. Objective This comprehensive review delves into the intricate relationship between CSCs and the cell-of-origin in diverse cancer types. Design Comprehensive review of thematically-relevant literature. Methods We explore the underlying molecular mechanisms that drive the conversion of normal cells into CSCs and the impact of the cell-of-origin on CSC properties, tumor initiation, and therapeutic responses. Moreover, we discuss potential therapeutic interventions targeting CSCs based on their distinct cell-of-origin characteristics. Results Accruing evidence suggest that the cell-of-origin, the cell type from which the tumor originates, plays a crucial role in determining the properties of CSCs and their contribution to tumor heterogeneity. Conclusion By providing critical insights into the complex interplay between CSCs and their cellular origins, this article aims to enhance our understanding of cancer biology and pave the way for more effective and personalized cancer treatments.
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Affiliation(s)
- Oluwaseun Adebayo Bamodu
- Directorate of Postgraduate Studies, School of Clinical Medicine, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
- Ocean Road Cancer Institute, Dar es Salaam, Tanzania
| | - Chen-Chih Chung
- Department of Neurology, Taipei Medical University - Shuang Ho Hospital, New Taipei City, Taiwan
- Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Taipei Neuroscience Institute, Taipei Medical University - Shuang Ho Hospital, New Taipei City, Taiwan
| | - Thomas R. Pisanic
- Johns Hopkins Institute for NanoBioTechnology, Baltimore, MD, United States
- Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Oncology - Cancer Genetics and Epigenetics, Johns Hopkins University, Baltimore, MD, United States
| | - Alexander T. H. Wu
- The Program for Translational Medicine, Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
- Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
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24
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Sloan AR, Silver DJ, Kint S, Gallo M, Lathia JD. Cancer stem cell hypothesis 2.0 in glioblastoma: Where are we now and where are we going? Neuro Oncol 2024; 26:785-795. [PMID: 38394444 PMCID: PMC11066900 DOI: 10.1093/neuonc/noae011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2024] Open
Abstract
Over the past 2 decades, the cancer stem cell (CSC) hypothesis has provided insight into many malignant tumors, including glioblastoma (GBM). Cancer stem cells have been identified in patient-derived tumors and in some mouse models, allowing for a deeper understanding of cellular and molecular mechanisms underlying GBM growth and therapeutic resistance. The CSC hypothesis has been the cornerstone of cellular heterogeneity, providing a conceptual and technical framework to explain this longstanding phenotype in GBM. This hypothesis has evolved to fit recent insights into how cellular plasticity drives tumor growth to suggest that CSCs do not represent a distinct population but rather a cellular state with substantial plasticity that can be achieved by non-CSCs under specific conditions. This has further been reinforced by advances in genomics, including single-cell approaches, that have used the CSC hypothesis to identify multiple putative CSC states with unique properties, including specific developmental and metabolic programs. In this review, we provide a historical perspective on the CSC hypothesis and its recent evolution, with a focus on key functional phenotypes, and provide an update on the definition for its use in future genomic studies.
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Affiliation(s)
- Anthony R Sloan
- Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Case Comprehensive Cancer Center, Cleveland, Ohio, USA
| | - Daniel J Silver
- Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Case Comprehensive Cancer Center, Cleveland, Ohio, USA
| | - Sam Kint
- Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Marco Gallo
- Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Pediatrics, Section of Hematology and Oncology, Baylor College of Medicine, Houston, Texas, USA
- Texas Children’s Cancer Center, Texas Children’s Hospital, Houston, Texas, USA
| | - Justin D Lathia
- Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Case Comprehensive Cancer Center, Cleveland, Ohio, USA
- Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio, USA
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25
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Débare H, Blanc F, Piton G, Leplat JJ, Vincent-Naulleau S, Rivière J, Vilotte M, Marthey S, Lecardonnel J, Coville JL, Estellé J, Rau A, Bourneuf E, Egidy G. Malignant features of minipig melanomas prior to spontaneous regression. Sci Rep 2024; 14:9240. [PMID: 38649394 PMCID: PMC11035550 DOI: 10.1038/s41598-024-59741-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 04/15/2024] [Indexed: 04/25/2024] Open
Abstract
In MeLiM minipigs, melanomas develop around birth, can metastasize, and have histopathologic characteristics similar to humans. Interestingly, MeLiM melanomas eventually regress. This favorable outcome raises the question of their malignancy, which we investigated. We clinically followed tens of tumors from onset to first signs of regression. Transcriptome analysis revealed an enrichment of all cancer hallmarks in melanomas, although no activating or suppressing somatic mutation were found in common driver genes. Analysis of tumor cell genomes revealed high mutation rates without UV signature. Canonical proliferative, survival and angiogenic pathways were detected in MeLiM tumor cells all along progression stages. Functionally, we show that MeLiM melanoma cells are capable to grow in immunocompromised mice, with serial passages and for a longer time than in MeLiM pigs. Pigs set in place an immune response during progression with dense infiltration by myeloid cells while melanoma cells are deficient in B2M expression. To conclude, our data on MeLiM melanomas reveal several malignancy characteristics. The combination of these features with the successful spontaneous regression of these tumors make it an outstanding model to study an efficient anti-tumor immune response.
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Affiliation(s)
- Héloïse Débare
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France
| | - Fany Blanc
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France
| | - Guillaume Piton
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France
- Université Paris-Saclay, CEA, Stabilité Génétique Cellules Souches Et Radiations, 92260, Fontenay-Aux-Roses, France
- Université de Paris Cité, CEA, Stabilité Génétique Cellules Souches Et Radiations, 92260, Fontenay-Aux-Roses, France
| | - Jean-Jacques Leplat
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France
- Université Paris-Saclay, CEA, Stabilité Génétique Cellules Souches Et Radiations, 92260, Fontenay-Aux-Roses, France
| | - Silvia Vincent-Naulleau
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France
- Université Paris-Saclay, CEA, Stabilité Génétique Cellules Souches Et Radiations, 92260, Fontenay-Aux-Roses, France
- Université de Paris Cité, CEA, Stabilité Génétique Cellules Souches Et Radiations, 92260, Fontenay-Aux-Roses, France
| | - Julie Rivière
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France
- Université Paris-Saclay, INRAE, AgroParisTech, Institut Micalis, 78350, Jouy-en-Josas, France
| | - Marthe Vilotte
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France
| | - Sylvain Marthey
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France
| | - Jérôme Lecardonnel
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France
| | - Jean-Luc Coville
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France
| | - Jordi Estellé
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France
| | - Andrea Rau
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France
| | - Emmanuelle Bourneuf
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France
- Université Paris-Saclay, CEA, Stabilité Génétique Cellules Souches Et Radiations, 92260, Fontenay-Aux-Roses, France
- Université de Paris Cité, CEA, Stabilité Génétique Cellules Souches Et Radiations, 92260, Fontenay-Aux-Roses, France
| | - Giorgia Egidy
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France.
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26
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Magrath JW, Goldberg IN, Truong DD, Hartono AB, Sampath SS, Jackson CE, Ghosh A, Cardin DL, Zhang H, Ludwig JA, Lee SB. Enzalutamide induces cytotoxicity in desmoplastic small round cell tumor independent of the androgen receptor. Commun Biol 2024; 7:411. [PMID: 38575753 PMCID: PMC10995187 DOI: 10.1038/s42003-024-06003-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 03/01/2024] [Indexed: 04/06/2024] Open
Abstract
Desmoplastic Small Round Cell Tumor (DSRCT) is a rare, pediatric cancer caused by the EWSR1::WT1 fusion protein. DSRCT predominantly occurs in males, which comprise 80-90% of the patient population. While the reason for this male predominance remains unknown, one hypothesis is that the androgen receptor (AR) plays a critical role in DSRCT and elevated testosterone levels in males help drive tumor growth. Here, we demonstrate that AR is highly expressed in DSRCT relative to other fusion-driven sarcomas and that the AR antagonists enzalutamide and flutamide reduce DSRCT growth. However, despite these findings, which suggest an important role for AR in DSRCT, we show that DSRCT cell lines form xenografts in female mice at the same rate as male mice and AR depletion does not significantly alter DSRCT growth in vitro. Further, we find that AR antagonists reduce DSRCT growth in cells depleted of AR, establishing an AR-independent mechanism of action. These findings suggest that AR dependence is not the reason for male predominance in DSRCT and that AR-targeted therapies may provide therapeutic benefit primarily through an AR-independent mechanism that requires further elucidation.
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Affiliation(s)
- Justin W Magrath
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, USA
| | - Ilon N Goldberg
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, USA
| | - Danh D Truong
- Sarcoma Medical Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Alifiani B Hartono
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, USA
| | - Shruthi Sanjitha Sampath
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, USA
| | - Chandler E Jackson
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, USA
| | - Anushka Ghosh
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, USA
| | - Derrick L Cardin
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, USA
| | - Haitao Zhang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, USA
| | - Joseph A Ludwig
- Sarcoma Medical Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Sean B Lee
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, USA.
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27
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Sud A, Parry EM, Wu CJ. The molecular map of CLL and Richter's syndrome. Semin Hematol 2024; 61:73-82. [PMID: 38368146 PMCID: PMC11653080 DOI: 10.1053/j.seminhematol.2024.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 01/16/2024] [Accepted: 01/20/2024] [Indexed: 02/19/2024]
Abstract
Clonal expansion of B-cells, from the early stages of monoclonal B-cell lymphocytosis through to chronic lymphocytic leukemia (CLL), and then in some cases to Richter's syndrome (RS) provides a comprehensive model of cancer evolution, notable for the marked morphological transformation and distinct clinical phenotypes. High-throughput sequencing of large cohorts of patients and single-cell studies have generated a molecular map of CLL and more recently, of RS, yielding fundamental insights into these diseases and of clonal evolution. A selection of CLL driver genes have been functionally interrogated to yield novel insights into the biology of CLL. Such findings have the potential to impact patient care through risk stratification, treatment selection and drug discovery. However, this molecular map remains incomplete, with extant questions concerning the origin of the B-cell clone, the role of the TME, inter- and intra-compartmental heterogeneity and of therapeutic resistance mechanisms. Through the application of multi-modal single-cell technologies across tissues, disease states and clinical contexts, these questions can now be addressed with the answers holding great promise of generating translatable knowledge to improve patient care.
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Affiliation(s)
- Amit Sud
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA; Broad Institute of MIT and Harvard, Cambridge, MA; Department of Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
| | - Erin M Parry
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA; Broad Institute of MIT and Harvard, Cambridge, MA.
| | - Catherine J Wu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA; Broad Institute of MIT and Harvard, Cambridge, MA; Department of Medicine, Brigham and Women's Hospital, Boston, MA
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28
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Atwani R, Rogers A, Nagare R, Prasad M, Lazar V, Sandusky G, Pin F, Condello S. Integrin-linked kinase-frizzled 7 interaction maintains cancer stem cells to drive platinum resistance in ovarian cancer. RESEARCH SQUARE 2024:rs.3.rs-4086737. [PMID: 38559125 PMCID: PMC10980163 DOI: 10.21203/rs.3.rs-4086737/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Background Platinum-based chemotherapy regimens are a mainstay in the management of ovarian cancer (OC), but emergence of chemoresistance poses a significant clinical challenge. The persistence of ovarian cancer stem cells (OCSCs) at the end of primary treatment contributes to disease recurrence. Here, we hypothesized that the extracellular matrix protects CSCs during chemotherapy and supports their tumorigenic functions by activating integrin-linked kinase (ILK), a key enzyme in drug resistance. Methods TCGA datasets and OC models were investigated using an integrated proteomic and gene expression analysis and examined ILK for correlations with chemoresistance pathways and clinical outcomes. Canonical Wnt pathway components, pro-survival signaling, and stemness were examined using OC models. To investigate the role of ILK in the OCSC-phenotype, a novel pharmacological inhibitor of ILK in combination with carboplatin was utilized in vitro and in vivo OC models. Results In response to increased fibronectin (FN) secretion and integrin β1 clustering, aberrant ILK activation supported the OCSC phenotype, contributing to OC spheroid proliferation and reduced response to platinum treatment. Complexes formed by ILK with the Wnt receptor frizzled 7 (Fzd7) were detected in tumors and showed a strong correlation with metastatic progression. Moreover, TCGA datasets confirmed that combined expression of ILK and Fzd7 in high grade serous ovarian tumors is correlated with reduced response to chemotherapy and poor patient outcomes. Mechanistically, interaction of ILK with Fzd7 increased the response to Wnt ligands, thereby amplifying the stemness-associated Wnt/β-catenin signaling. Notably, preclinical studies showed that the novel ILK inhibitor compound 22 (cpd-22) alone disrupted ILK interaction with Fzd7 and CSC proliferation as spheroids. Furthermore, when combined with carboplatin, this disruption led to sustained AKT inhibition, apoptotic damage in OCSCs and reduced tumorigenicity in mice. Conclusions This "outside-in" signaling mechanism is potentially actionable, and combined targeting of ILK-Fzd7 may represent a new therapeutic strategy to eradicate OCSCs and improve patient outcomes.
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29
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Knopik-Skrocka A, Sempowicz A, Piwocka O. Plasticity and resistance of cancer stem cells as a challenge for innovative anticancer therapies - do we know enough to overcome this? EXCLI JOURNAL 2024; 23:335-355. [PMID: 38655094 PMCID: PMC11036066 DOI: 10.17179/excli2024-6972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 02/20/2024] [Indexed: 04/26/2024]
Abstract
According to the CSC hypothesis, cancer stem cells are pivotal in initiating, developing, and causing cancer recurrence. Since the identification of CSCs in leukemia, breast cancer, glioblastoma, and colorectal cancer in the 1990s, researchers have actively investigated the origin and biology of CSCs. However, the CSC hypothesis and the role of these cells in tumor development model is still in debate. These cells exhibit distinct surface markers, are capable of self-renewal, demonstrate unrestricted proliferation, and display metabolic adaptation. CSC phenotypic plasticity and the capacity to EMT is strictly connected to the stemness state. CSCs show high resistance to chemotherapy, radiotherapy, and immunotherapy. The plasticity of CSCs is significantly influenced by tumor microenvironment factors, such as hypoxia. Targeting the genetic and epigenetic changes of cancer cells, together with interactions with the tumor microenvironment, presents promising avenues for therapeutic strategies. See also the Graphical abstract(Fig. 1).
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Affiliation(s)
- Agnieszka Knopik-Skrocka
- Department of Cell Biology, Faculty of Biology, Adam Mickiewicz University of Poznań, Poland
- Section of Regenerative Medicine and Cancer Research, Natural Sciences Club, Faculty of Biology, Adam Mickiewicz University, 61-614 Poznań, Poland
| | - Alicja Sempowicz
- Department of Cell Biology, Faculty of Biology, Adam Mickiewicz University of Poznań, Poland
- Section of Regenerative Medicine and Cancer Research, Natural Sciences Club, Faculty of Biology, Adam Mickiewicz University, 61-614 Poznań, Poland
| | - Oliwia Piwocka
- Radiobiology Laboratory, Department of Medical Physics, Greater Poland Cancer Center, Poznań, Poland
- Department of Electroradiology, Poznan University of Medical Sciences, Poznań, Poland
- Doctoral School, Poznan University of Medical Sciences, Poznań, Poland
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30
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Singvogel K, Schittek B. Dormancy of cutaneous melanoma. Cancer Cell Int 2024; 24:88. [PMID: 38419052 PMCID: PMC10903048 DOI: 10.1186/s12935-024-03278-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 02/19/2024] [Indexed: 03/02/2024] Open
Abstract
Many cancer-related deaths including melanoma result from metastases that develop months or years after the initial cancer therapy. Even the most effective drugs and immune therapies rarely eradicate all tumor cells. Instead, they strongly reduce cancer burden, permitting dormant cancer cells to persist in niches, where they establish a cellular homeostasis with their host without causing clinical symptoms. Dormant cancers respond poorly to most drugs and therapies since they do not proliferate and hide in niches. It therefore remains a major challenge to develop novel therapies for dormant cancers. In this review we focus on the mechanisms regulating the initiation of cutaneous melanoma dormancy as well as those which are involved in reawakening of dormant cutaneous melanoma cells. In recent years the role of neutrophils and niche components in reawakening of melanoma cells came into focus and indicate possible future therapeutic applications. Sophisticated in vitro and in vivo melanoma dormancy models are needed to make progress in this field and are discussed.
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Affiliation(s)
- Kathrin Singvogel
- Division of Dermatooncology, Department of Dermatology, University of Tübingen, Liebermeisterstr. 25, D -72076 , Tübingen, Germany
| | - Birgit Schittek
- Division of Dermatooncology, Department of Dermatology, University of Tübingen, Liebermeisterstr. 25, D -72076 , Tübingen, Germany.
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany.
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31
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Habowski AN, Budagavi DP, Scherer SD, Aurora AB, Caligiuri G, Flynn WF, Langer EM, Brody JR, Sears RC, Foggetti G, Arnal Estape A, Nguyen DX, Politi KA, Shen X, Hsu DS, Peehl DM, Kurhanewicz J, Sriram R, Suarez M, Xiao S, Du Y, Li XN, Navone NM, Labanca E, Willey CD. Patient-Derived Models of Cancer in the NCI PDMC Consortium: Selection, Pitfalls, and Practical Recommendations. Cancers (Basel) 2024; 16:565. [PMID: 38339316 PMCID: PMC10854945 DOI: 10.3390/cancers16030565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/16/2024] [Accepted: 01/20/2024] [Indexed: 02/12/2024] Open
Abstract
For over a century, early researchers sought to study biological organisms in a laboratory setting, leading to the generation of both in vitro and in vivo model systems. Patient-derived models of cancer (PDMCs) have more recently come to the forefront of preclinical cancer models and are even finding their way into clinical practice as part of functional precision medicine programs. The PDMC Consortium, supported by the Division of Cancer Biology in the National Cancer Institute of the National Institutes of Health, seeks to understand the biological principles that govern the various PDMC behaviors, particularly in response to perturbagens, such as cancer therapeutics. Based on collective experience from the consortium groups, we provide insight regarding PDMCs established both in vitro and in vivo, with a focus on practical matters related to developing and maintaining key cancer models through a series of vignettes. Although every model has the potential to offer valuable insights, the choice of the right model should be guided by the research question. However, recognizing the inherent constraints in each model is crucial. Our objective here is to delineate the strengths and limitations of each model as established by individual vignettes. Further advances in PDMCs and the development of novel model systems will enable us to better understand human biology and improve the study of human pathology in the lab.
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Affiliation(s)
- Amber N. Habowski
- Cold Spring Harbor Laboratory, Long Island, NY 11724, USA; (A.N.H.); (D.P.B.); (G.C.)
| | - Deepthi P. Budagavi
- Cold Spring Harbor Laboratory, Long Island, NY 11724, USA; (A.N.H.); (D.P.B.); (G.C.)
| | - Sandra D. Scherer
- Department of Oncologic Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA;
| | - Arin B. Aurora
- Children’s Research Institute and Department of Pediatrics, University of Texas Southwestern, Dallas, TX 75235, USA;
| | - Giuseppina Caligiuri
- Cold Spring Harbor Laboratory, Long Island, NY 11724, USA; (A.N.H.); (D.P.B.); (G.C.)
| | | | - Ellen M. Langer
- Division of Oncological Sciences, Oregon Health & Science University, Portland, OR 97239, USA;
| | - Jonathan R. Brody
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA;
| | - Rosalie C. Sears
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA;
| | | | - Anna Arnal Estape
- Department of Internal Medicine, Yale University, New Haven, CT 06520, USA;
| | - Don X. Nguyen
- Department of Pathology, Yale University, New Haven, CT 06520, USA; (D.X.N.); (K.A.P.)
| | - Katerina A. Politi
- Department of Pathology, Yale University, New Haven, CT 06520, USA; (D.X.N.); (K.A.P.)
| | - Xiling Shen
- Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90024, USA;
| | - David S. Hsu
- Department of Medicine, Duke University, Durham, NC 27710, USA;
| | - Donna M. Peehl
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94158, USA; (D.M.P.); (J.K.); (R.S.)
| | - John Kurhanewicz
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94158, USA; (D.M.P.); (J.K.); (R.S.)
| | - Renuka Sriram
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94158, USA; (D.M.P.); (J.K.); (R.S.)
| | - Milagros Suarez
- Department of Pediatrics, Lurie Children’s Hospital of Chicago Northwestern University, Chicago, IL 60611, USA; (M.S.); (S.X.); (Y.D.); (X.-N.L.)
| | - Sophie Xiao
- Department of Pediatrics, Lurie Children’s Hospital of Chicago Northwestern University, Chicago, IL 60611, USA; (M.S.); (S.X.); (Y.D.); (X.-N.L.)
| | - Yuchen Du
- Department of Pediatrics, Lurie Children’s Hospital of Chicago Northwestern University, Chicago, IL 60611, USA; (M.S.); (S.X.); (Y.D.); (X.-N.L.)
| | - Xiao-Nan Li
- Department of Pediatrics, Lurie Children’s Hospital of Chicago Northwestern University, Chicago, IL 60611, USA; (M.S.); (S.X.); (Y.D.); (X.-N.L.)
| | - Nora M. Navone
- Department of Genitourinary Medical Oncology, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (N.M.N.)
| | - Estefania Labanca
- Department of Genitourinary Medical Oncology, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (N.M.N.)
| | - Christopher D. Willey
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
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32
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Vogel FCE, Chaves-Filho AB, Schulze A. Lipids as mediators of cancer progression and metastasis. NATURE CANCER 2024; 5:16-29. [PMID: 38273023 DOI: 10.1038/s43018-023-00702-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 11/08/2023] [Indexed: 01/27/2024]
Abstract
Metastasis formation is a complex process, involving multiple crucial steps, which are controlled by different regulatory mechanisms. In this context, the contribution of cancer metabolism to the metastatic cascade is being increasingly recognized. This Review focuses on changes in lipid metabolism that contribute to metastasis formation in solid tumors. We discuss the molecular mechanisms by which lipids induce a pro-metastatic phenotype and explore the role of lipids in response to oxidative stress and as signaling molecules. Finally, we reflect on potential avenues to target lipid metabolism to improve the treatment of metastatic cancers.
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Affiliation(s)
- Felix C E Vogel
- Division of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
| | - Adriano B Chaves-Filho
- Division of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| | - Almut Schulze
- Division of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany.
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33
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Fernandes Q, Therachiyil L, Khan AQ, Bedhiafi T, Korashy HM, Bhat AA, Uddin S. Shrinking the battlefield in cancer therapy: Nanotechnology against cancer stem cells. Eur J Pharm Sci 2023; 191:106586. [PMID: 37729956 DOI: 10.1016/j.ejps.2023.106586] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 09/07/2023] [Accepted: 09/18/2023] [Indexed: 09/22/2023]
Abstract
Cancer remains one of the leading causes of mortality worldwide, presenting a significant healthcare challenge owing to the limited efficacy of current treatments. The application of nanotechnology in cancer treatment leverages the unique optical, magnetic, and electrical attributes of nanomaterials to engineer innovative, targeted therapies. Specifically, manipulating nanomaterials allows for enhanced drug loading efficiency, improved bioavailability, and targeted delivery systems, reducing the non-specific cytotoxic effects characteristic of conventional chemotherapies. Furthermore, recent advances in nanotechnology have demonstrated encouraging results in specifically targeting CSCs, a key development considering the role of these cells in disease recurrence and resistance to treatment. Despite these breakthroughs, the clinical approval rates of nano-drugs have not kept pace with research advances, pointing to existing obstacles that must be addressed. In conclusion, nanotechnology presents a novel, powerful tool in the fight against cancer, particularly in targeting the elusive and treatment-resistant CSCs. This comprehensive review delves into the intricacies of nanotherapy, explicitly targeting cancer stem cells, their markers, and associated signaling pathways.
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Affiliation(s)
- Queenie Fernandes
- College of Medicine, Qatar University, Doha, Qatar; Translational Cancer Research Facility, Hamad Medical Corporation, National Center for Cancer Care and Research, PO. Box 3050, Doha, Qatar
| | - Lubna Therachiyil
- Academic Health System, Hamad Medical Corporation, Translational Research Institute, Doha 3050, Qatar; Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha 2713, Qatar
| | - Abdul Q Khan
- Academic Health System, Hamad Medical Corporation, Translational Research Institute, Doha 3050, Qatar
| | - Takwa Bedhiafi
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha 2713, Qatar
| | - Hesham M Korashy
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha 2713, Qatar
| | - Ajaz A Bhat
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Shahab Uddin
- College of Medicine, Qatar University, Doha, Qatar; Academic Health System, Hamad Medical Corporation, Dermatology Institute, Doha 3050, Qatar; Laboratory of Animal Research Center, Qatar University, Doha 2713, Qatar; Department of Biosciences, Integral University, Lucknow, Uttar Pradesh 22602, India.
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34
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Magrath JW, Goldberg IN, Truong DD, Hartono AB, Sampath SS, Jackson CE, Ghosh A, Cardin DL, Zhang H, Ludwig JA, Lee SB. Enzalutamide Induces Cytotoxicity in Desmoplastic Small Round Cell Tumor Independent of the Androgen Receptor. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.06.565842. [PMID: 37986851 PMCID: PMC10659336 DOI: 10.1101/2023.11.06.565842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2023]
Abstract
Desmoplastic Small Round Cell Tumor (DSRCT) is a rare, pediatric cancer caused by the EWSR1::WT1 fusion protein. DSRCT predominantly occurs in males, which comprise 80-90% of the patient population. While the reason for this male predominance remains unknown, one hypothesis is that the androgen receptor (AR) plays a critical role in DSRCT and elevated testosterone levels in males help drive tumor growth. Here, we demonstrate that AR is highly expressed in DSRCT relative to other fusion-driven sarcomas and that the AR antagonists enzalutamide and flutamide reduce DSRCT growth. However, despite these findings, which suggest an important role for AR in DSRCT, we show that DSRCT cell lines form xenografts in female mice at the same rate as male mice and AR depletion does not significantly alter DSRCT growth in vitro. Further, we find that AR antagonists reduce DSRCT growth in cells depleted of AR, establishing an AR-independent mechanism of action. These findings suggest that AR dependence is not the reason for male predominance in DSRCT and that AR-targeted therapies may provide therapeutic benefit primarily through an AR-independent mechanism that requires further elucidation.
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Affiliation(s)
- Justin W Magrath
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | - Ilon N Goldberg
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | - Danh D Truong
- Sarcoma Medical Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Alifiani B Hartono
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | - Shruthi Sanjitha Sampath
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | - Chandler E Jackson
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | - Anushka Ghosh
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | - Derrick L Cardin
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | - Haitao Zhang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
| | - Joseph A Ludwig
- Sarcoma Medical Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Sean B Lee
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA
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35
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Wang B, Wei CY, Wang KW, Fu B, Chen Y, Han Y, Zhang Z. Fabrication of near infrared light responsive photoelectrochemical immunosensor for in vivo detection of melanoma cells. Biosens Bioelectron 2023; 239:115601. [PMID: 37633000 DOI: 10.1016/j.bios.2023.115601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 07/24/2023] [Accepted: 08/13/2023] [Indexed: 08/28/2023]
Abstract
Effective and convenient detection of melanoma cells with high sensitivity is essential to identify malignant melanoma in its early stage. However, the existing detection methods, such as immunohistochemical analysis, are too complicated and time-consuming to realize the convenient in vivo and in situ detection. Herein, a near infrared responsive photoelectrochemical (PEC) immunosensor is proposed with plasmonic Au nanoparticles-photonic TiO2 nanocaves (Au/TiO2 NCs) as photon harvest and conversion transducer and antibody as cell recognition unit. The micro-antibody/Au/TiO2 NCs photoelectrode can easily in vivo distinguish melanoma cells and can realize sensitive detection of melanoma cells in short time of 1 min with a lowest limit of detection of 2 cell mL-1. The PEC immunosensor strategy not only allows us to pioneeringly implement sensitive in vivo bio-detection, but also opens up a new avenue for rational design of cell recognition units and micro-electrode for universal and reliable bio-detections.
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Affiliation(s)
- Bing Wang
- Department of Oncological Surgery, Minhang Branch, Shanghai Cancer Center, Fudan University, Shanghai, 200240, China
| | - Chuan-Yuan Wei
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Kang-Wei Wang
- Department of Oncological Surgery, Minhang Branch, Shanghai Cancer Center, Fudan University, Shanghai, 200240, China
| | - Baihe Fu
- School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200241, China
| | - Yong Chen
- Department of Oncological Surgery, Minhang Branch, Shanghai Cancer Center, Fudan University, Shanghai, 200240, China; Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Fudan University Shanghai Medical School, Shanghai, 200032, China.
| | - Yu Han
- Department of Oncological Surgery, Minhang Branch, Shanghai Cancer Center, Fudan University, Shanghai, 200240, China.
| | - Zhonghai Zhang
- School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200241, China.
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36
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Li Z, Gu H, Xu X, Tian Y, Huang X, Du Y. Unveiling the novel immune and molecular signatures of ovarian cancer: insights and innovations from single-cell sequencing. Front Immunol 2023; 14:1288027. [PMID: 38022625 PMCID: PMC10654630 DOI: 10.3389/fimmu.2023.1288027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 10/20/2023] [Indexed: 12/01/2023] Open
Abstract
Ovarian cancer is a highly heterogeneous and lethal malignancy with limited treatment options. Over the past decade, single-cell sequencing has emerged as an advanced biological technology capable of decoding the landscape of ovarian cancer at the single-cell resolution. It operates at the level of genes, transcriptomes, proteins, epigenomes, and metabolisms, providing detailed information that is distinct from bulk sequencing methods, which only offer average data for specific lesions. Single-cell sequencing technology provides detailed insights into the immune and molecular mechanisms underlying tumor occurrence, development, drug resistance, and immune escape. These insights can guide the development of innovative diagnostic markers, therapeutic strategies, and prognostic indicators. Overall, this review provides a comprehensive summary of the diverse applications of single-cell sequencing in ovarian cancer. It encompasses the identification and characterization of novel cell subpopulations, the elucidation of tumor heterogeneity, the investigation of the tumor microenvironment, the analysis of mechanisms underlying metastasis, and the integration of innovative approaches such as organoid models and multi-omics analysis.
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Affiliation(s)
- Zhongkang Li
- Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Haihan Gu
- Department of Pharmacy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiaotong Xu
- Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yanpeng Tian
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xianghua Huang
- Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yanfang Du
- Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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Wada H, Otsuka R, Germeraad WTV, Murata T, Kondo T, Seino KI. Tumor cell-induced macrophage senescence plays a pivotal role in tumor initiation followed by stable growth in immunocompetent condition. J Immunother Cancer 2023; 11:e006677. [PMID: 37963635 PMCID: PMC10649871 DOI: 10.1136/jitc-2023-006677] [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] [Accepted: 10/06/2023] [Indexed: 11/16/2023] Open
Abstract
BACKGROUND The cancer stem cell theory proposes that tumor formation in vivo is driven only by specific tumor-initiating cells having stemness; however, clinical trials conducted to test drugs that target the tumor stemness provided unsatisfactory results thus far. Recent studies showed clear involvement of immunity in tumors; however, the requirements of tumor-initiation followed by stable growth in immunocompetent individuals remain largely unknown. METHODS To clarify this, we used two similarly induced glioblastoma lines, 8B and 9G. They were both established by overexpression of an oncogenic H-RasL61 in p53-deficient neural stem cells. In immunocompromised animals in an orthotopic transplantation model using 1000 cells, both show tumor-forming potential. On the other hand, although in immunocompetent animals, 8B shows similar tumor-forming potential but that of 9G's are very poor. This suggests that 8B cells are tumor-initiating cells in immunocompetent animals. Therefore, we hypothesized that the differences in the interaction properties of 8B and 9G with immune cells could be used to identify the factors responsible for its tumor forming potential in immunocompetent animals and performed analysis. RESULTS Different from 9G, 8B cells induced senescence-like state of macrophages around tumors. We investigated the senescence-inducing factor of macrophages by 8B cells and found that it was interleukin 6. Such senescence-like macrophages produced Arginase-1, an immunosuppressive molecule known to contribute to T-cell hyporesponsiveness. The senescence-like macrophages highly expressed CD38, a nicotinamide adenine dinucleotide (NAD) glycohydrolase associated with NAD shortage in senescent cells. The addition of nicotinamide mononucleotide (NMN), an NAD precursor, in vitro inhibited to the induction of macrophage senescence-like phenotype and inhibited Arginase-1 expression resulting in retaining T-cell function. Moreover, exogenous in vivo administration of NMN after tumor inoculation inhibited tumor-initiation followed by stable growth in the immunocompetent mouse tumor model. CONCLUSIONS We identified one of the requirements for tumor-initiating cells in immunocompetent animals. In addition, we have shown that tumor growth can be inhibited by externally administered NMN against macrophage senescence-like state that occurs in the very early stages of tumor-initiating cell development. This therapy targeting the immunosuppressive environment formed by macrophage senescence-like state is expected to be a novel promising cancer therapeutic strategy.
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Affiliation(s)
- Haruka Wada
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Ryo Otsuka
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Wilfred T V Germeraad
- GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, Limburg, The Netherlands
- Department of Internal Medicine, Division of Hematology, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Tomoki Murata
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Toru Kondo
- Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Ken-Ichiro Seino
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
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Bushnell GG, Sharma D, Wilmot HC, Zheng M, Fashina TD, Hutchens CM, Osipov S, Wicha MS. Natural killer cell regulation of breast cancer stem cells mediates metastatic dormancy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.02.560493. [PMID: 37873211 PMCID: PMC10592904 DOI: 10.1101/2023.10.02.560493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Breast cancer patients with estrogen receptor positive tumors face a constant risk of disease recurrence for the remainder of their lives. Dormant tumor cells residing in tissues such as the bone marrow may generate clinically significant metastases many years after initial diagnosis. Previous studies suggest that dormant cells display "stem like" properties (CSCs), which may be regulated by the immune system. Although many studies have examined tumor cell intrinsic characteristics of dormancy, the role of the immune system in controlling dormancy and its escape is not well understood. This scientific gap is due, in part, to a lack of immunocompetent mouse models of breast cancer dormancy with many studies involving human xenografts in immunodeficient mice. To overcome this limitation, we studied dormancy in immunocompetent, syngeneic mouse breast cancer models. We find that PyMT, Met-1 and D2.0R cell lines contain CSCs that display both short- and long-term metastatic dormancy in vivo, which is dependent on the host immune system. Natural killer cells were key for the metastatic dormancy phenotype observed for D2.0R and the role of NK cells in regulating CSCs was further investigated.Quiescent D2.0R CSC are resistant to NK cytotoxicity, while proliferative D2.0R CSC were sensitive to NK cytotoxicity both in vitro and in vivo. This resistance was mediated, in part, by the expression of Bach1 and Sox2 transcription factors. NK killing was enhanced by the STING agonist MSA-2. Collectively, our findings demonstrate the important role of immune regulation of breast tumor dormancy and highlight the importance of utilizing immunocompetent models to study this phenomenon.
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Kim Y, Tram LTH, Kim KA, Kim BC. Defining Integrin Tension Required for Chemotaxis of Metastatic Breast Cancer Cells in Confinement. Adv Healthc Mater 2023; 12:e2202747. [PMID: 37256848 DOI: 10.1002/adhm.202202747] [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: 11/13/2022] [Revised: 05/21/2023] [Indexed: 06/02/2023]
Abstract
Cancer metastasis is affected by chemical factors and physical cues. From cell adhesion to migration, mechanical tension applied to integrin expresses on the cell membrane and physical confinement significantly regulates cancer cell behaviors. Despite the physical interplay between integrins in cells and ligands in the tumor microenvironment, quantitative analysis of integrin tension during cancer cell migration in microconfined spaces remains elusive owing to the limited experimental tools. Herein, a platform termed microconfinement tension gauge tether to monitor spatial integrin tension with single-molecule precision by analyzing the epithelial-growth-factor-induced chemotaxis of metastatic human breast cancer cells in microfluidic channels is developed. The results reveal that the metastatic cancer cells exert the strongest integrin tension in the range of 54-100 pN at the leading edges of cells during chemokinetic migration on a planar surface, while the cells exert the strongest integrin tension exceeding 100 pN at the cell rear when entering microconfinement. Further analysis demonstrates that cells undergo mesenchymal migration under high integrin tension and less confinement, which is converted to amoeboid migration under low integrin tension or high confinement. In summary, the results identify a basic mechanism underlying the mechanical interactions between integrin tension and microenvironment that determines cancer invasion and metastasis.
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Affiliation(s)
- Young Kim
- Department of Nano-bioengineering, Incheon National University, Incheon, 22012, Republic of Korea
| | - Le Thi Hong Tram
- Department of Nano-bioengineering, Incheon National University, Incheon, 22012, Republic of Korea
| | - Kyung Ah Kim
- Department of Nano-bioengineering, Incheon National University, Incheon, 22012, Republic of Korea
| | - Byoung Choul Kim
- Department of Nano-bioengineering, Incheon National University, Incheon, 22012, Republic of Korea
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40
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Lam SSN, Shi Z, Ip CKM, Wong CKC, Wong AST. Environmental-relevant bisphenol A exposure promotes ovarian cancer stemness by regulating microRNA biogenesis. J Cell Mol Med 2023; 27:2792-2803. [PMID: 37610061 PMCID: PMC10494296 DOI: 10.1111/jcmm.17920] [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: 10/19/2022] [Revised: 08/04/2023] [Accepted: 08/11/2023] [Indexed: 08/24/2023] Open
Abstract
Bisphenol A (BPA) is a ubiquitous environmental xenobiotic impacting millions of people worldwide. BPA has long been proposed to promote ovarian carcinogenesis, but the detrimental mechanistic target remains unclear. Cancer stem cells (CSCs) are considered as the trigger of tumour initiation and progression. Here, we show for the first time that nanomolar (environmentally relevant) concentration of BPA can markedly increase the formation and expansion of ovarian CSCs concomitant. This effect is observed in both oestrogen receptor (ER)-positive and ER-defective ovarian cancer cells, suggesting that is independent of the classical ERs. Rather, the signal is mediated through alternative ER G-protein-coupled receptor 30 (GPR30), but not oestrogen-related receptor α and γ. Moreover, we report a novel role of BPA in the regulation of Exportin-5 that led to dysregulation of microRNA biogenesis through miR-21. The use of GPR30 siRNA or antagonist to inhibit GPR30 expression or activity, respectively, resulted in significant inhibition of ovarian CSCs. Similarly, the CSCs phenotype can be reversed by expression of Exportin-5 siRNA. These results identify for the first time non-classical ER and microRNA dysregulation as novel mediators of low, physiological levels of BPA function in CSCs that may underlie its significant tumour-promoting properties in ovarian cancer.
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Affiliation(s)
- Sophia S. N. Lam
- School of Biological SciencesUniversity of Hong KongHong KongChina
- Laboratory for Synthetic Chemistry and Chemical Biology LimitedHong Kong Science and Technology ParksHong KongChina
| | - Zeyu Shi
- School of Biological SciencesUniversity of Hong KongHong KongChina
- Laboratory for Synthetic Chemistry and Chemical Biology LimitedHong Kong Science and Technology ParksHong KongChina
| | - Carman K. M. Ip
- Cellular Screening CenterUniversity of ChicagoChicagoIllinoisUSA
| | | | - Alice S. T. Wong
- School of Biological SciencesUniversity of Hong KongHong KongChina
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Balakin VE, Rozanova OM, Smirnova EN, Belyakova TA, Strelnikova NS, Smirnov AV, Shemyakov AE. Growth Induction of Solid Ehrlich Ascitic Carcinoma in Mice after Proton Irradiation of Tumor Cells Ex Vivo. DOKL BIOCHEM BIOPHYS 2023; 511:151-155. [PMID: 37833598 DOI: 10.1134/s1607672923700229] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/21/2023] [Accepted: 03/21/2023] [Indexed: 10/15/2023]
Abstract
This study presents data on the growth rate and frequency of induction of the solid form of Ehrlich's ascites carcinoma (EAC) in mice in the short and long term after inoculation of ascitic cells irradiated ex vivo with a proton beam in the dose range of 30-150 Gy. It was shown that the growth rate of solid tumors after inoculation of irradiated cells ex vivo coincided with the growth of tumors in the control group. The frequency of tumor induction in mice after inoculation of EAC cells irradiated at a dose of 30 Gy was 80%, 60 Gy-60%, 90 Gy-25%, and 120 Gy-10%; at irradiation at a dose of 150 Gy, no tumors appeared during the entire observation period. Thus, we determined the dose of proton radiation required to eliminate tumor cells and/or signaling factors that can lead to the induction of tumor growth of EAC in mice.
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Affiliation(s)
- V E Balakin
- Physical-Technical Center, Branch of Lebedev Physical Institute, Russian Academy of Sciences, Protvino, Russia
| | - O M Rozanova
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia
| | - E N Smirnova
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia
| | - T A Belyakova
- Physical-Technical Center, Branch of Lebedev Physical Institute, Russian Academy of Sciences, Protvino, Russia
| | - N S Strelnikova
- Physical-Technical Center, Branch of Lebedev Physical Institute, Russian Academy of Sciences, Protvino, Russia.
| | - A V Smirnov
- Physical-Technical Center, Branch of Lebedev Physical Institute, Russian Academy of Sciences, Protvino, Russia
| | - A E Shemyakov
- Physical-Technical Center, Branch of Lebedev Physical Institute, Russian Academy of Sciences, Protvino, Russia
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Pérez-González A, Bévant K, Blanpain C. Cancer cell plasticity during tumor progression, metastasis and response to therapy. NATURE CANCER 2023; 4:1063-1082. [PMID: 37537300 PMCID: PMC7615147 DOI: 10.1038/s43018-023-00595-y] [Citation(s) in RCA: 110] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 06/01/2023] [Indexed: 08/05/2023]
Abstract
Cell plasticity represents the ability of cells to be reprogrammed and to change their fate and identity, enabling homeostasis restoration and tissue regeneration following damage. Cell plasticity also contributes to pathological conditions, such as cancer, enabling cells to acquire new phenotypic and functional features by transiting across distinct cell states that contribute to tumor initiation, progression, metastasis and resistance to therapy. Here, we review the intrinsic and extrinsic mechanisms driving cell plasticity that promote tumor growth and proliferation as well as metastasis and drug tolerance. Finally, we discuss how cell plasticity could be exploited for anti-cancer therapy.
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Affiliation(s)
- Andrea Pérez-González
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Kevin Bévant
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Cédric Blanpain
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium.
- WELBIO, ULB, Bruxelles, Belgium.
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Brown G. Deregulation of All- Trans Retinoic Acid Signaling and Development in Cancer. Int J Mol Sci 2023; 24:12089. [PMID: 37569466 PMCID: PMC10419198 DOI: 10.3390/ijms241512089] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 07/25/2023] [Accepted: 07/27/2023] [Indexed: 08/13/2023] Open
Abstract
Cancer stem cells are the root cause of cancer, which, in essence, is a developmental disorder. All-trans retinoic acid (ATRA) signaling via ligand-activation of the retinoic acid receptors (RARs) plays a crucial role in tissue patterning and development during mammalian embryogenesis. In adults, active RARγ maintains the pool of hematopoietic stem cells, whereas active RARα drives myeloid cell differentiation. Various findings have revealed that ATRA signaling is deregulated in many cancers. The enzymes for ATRA synthesis are downregulated in colorectal, gastric, lung, and oropharyngeal cancers. ATRA levels within breast, ovarian, pancreatic, prostate, and renal cancer cells were lower than within their normal counterpart cells. The importance is that 0.24 nM ATRA activates RARγ (for stem cell stemness), whereas 100 times more is required to activate RARα (for differentiation). Moreover, RARγ is an oncogene regarding overexpression within colorectal, cholangiocarcinoma, hepatocellular, ovarian, pancreatic, and renal cancer cells. The microRNA (miR) 30a-5p downregulates expression of RARγ, and miR-30a/miR-30a-5p is a tumor suppressor for breast, colorectal, gastric, hepatocellular, lung, oropharyngeal, ovarian, pancreatic, prostate, and renal cancer. These complementary findings support the view that perturbations to ATRA signaling play a role in driving the abnormal behavior of cancer stem cells. Targeting ATRA synthesis and RARγ has provided promising approaches to eliminating cancer stem cells because such agents have been shown to drive cell death.
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Affiliation(s)
- Geoffrey Brown
- School of Biomedical Sciences, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
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Valent P, Sadovnik I, Peter B, Ivanov D, Schulenburg A, Hadzijusufovic E, Willmann M, Rülicke T, Herrmann H, Rabitsch W, Karlic H, Gleixner KV, Sperr WR, Hoermann G, Dahlhoff M, Pfeilstöcker M, Keil F, Lion T, Grunt TW. Vienna Cancer Stem Cell Club (VCSCC): 20 year jubilee and future perspectives. Expert Rev Hematol 2023; 16:659-670. [PMID: 37493441 DOI: 10.1080/17474086.2023.2232545] [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: 04/03/2023] [Accepted: 06/29/2023] [Indexed: 07/27/2023]
Abstract
INTRODUCTION The Vienna Cancer Stem Cell Club (VCSCC) was launched by a group of scientists in Vienna in 2002. AREAS COVERED Major aims of the VCSCC are to support research on cancer stem cells (CSC) in hematopoietic malignancies and to translate CSC-related markers and targets into clinical application. A primary focus of research in the VCSCC is the leukemic stem cell (LSC). Between 2013 and 2021, members of the VCSCC established a special research program on myeloproliferative neoplasms and since 2008, members of the VCSCC run the Ludwig Boltzmann Institute for Hematology and Oncology. In all these years, the VCSCC provided a robust intellectual platform for translational hematology and LSC research in Vienna. Furthermore, the VCSCC interacts with several national and international study groups and societies in the field. Representatives of the VCSCC also organized a number of international meetings and conferences on neoplastic stem cells, including LSC, in the past 15 years, and contributed to the definition and classification of CSC/LSC and related pre-malignant and malignant conditions. EXPERT OPINION The VCSCC will continue to advance the field and to develop LSC-detecting and LSC-eradicating concepts through which diagnosis, prognostication, and therapy of blood cancer patients should improve.
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Affiliation(s)
- Peter Valent
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - Irina Sadovnik
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - Barbara Peter
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
| | - Daniel Ivanov
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - Axel Schulenburg
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Department of Internal Medicine I, Stem Cell Transplantation Unit, Medical University of Vienna, Vienna, Austria
| | - Emir Hadzijusufovic
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
- Department for Companion Animals and Horses, University Clinic for Small Animals, Internal Medicine Small Animals, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Michael Willmann
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Department for Companion Animals and Horses, University Clinic for Small Animals, Internal Medicine Small Animals, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Thomas Rülicke
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Institute of in vivo and in vitro Models, Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Harald Herrmann
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Department of Radiation Oncology, Medical University of Vienna, Vienna, Austria
| | - Werner Rabitsch
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Department of Internal Medicine I, Stem Cell Transplantation Unit, Medical University of Vienna, Vienna, Austria
| | - Heidrun Karlic
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
| | - Karoline V Gleixner
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - Wolfgang R Sperr
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - Gregor Hoermann
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- MLL Munich Leukemia Laboratory, Munich, Germany
| | - Maik Dahlhoff
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Institute of in vivo and in vitro Models, Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Michael Pfeilstöcker
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Third Medical Department for Hematology and Oncology, Hanusch Hospital, Vienna, Austria
| | - Felix Keil
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Third Medical Department for Hematology and Oncology, Hanusch Hospital, Vienna, Austria
| | - Thomas Lion
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- St.Anna Children´s Cancer Research Institute (CCRI), Vienna, Austria
| | - Thomas W Grunt
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Department of Internal Medicine I, Division of Clinical Oncology, Medical University of Vienna, Vienna, Austria
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Yen BL, Hsieh CC, Hsu PJ, Chang CC, Wang LT, Yen ML. Three-Dimensional Spheroid Culture of Human Mesenchymal Stem Cells: Offering Therapeutic Advantages and In Vitro Glimpses of the In Vivo State. Stem Cells Transl Med 2023; 12:235-244. [PMID: 37184894 PMCID: PMC10184701 DOI: 10.1093/stcltm/szad011] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 02/06/2023] [Indexed: 05/16/2023] Open
Abstract
As invaluable as the standard 2-dimensional (2D) monolayer in vitro cell culture system has been, there is increasing evidence that 3-dimensional (3D) non-adherent conditions are more relevant to the in vivo condition. While one of the criteria for human mesenchymal stem cells (MSCs) has been in vitro plastic adherence, such 2D culture conditions are not representative of in vivo cell-cell and cell-extracellular matrix (ECM) interactions, which may be especially important for this progenitor/stem cell of skeletal and connective tissues. The 3D spheroid, a multicellular aggregate formed under non-adherent 3D in vitro conditions, may be particularly suited as an in vitro method to better understand MSC physiological processes, since expression of ECM and other adhesion proteins are upregulated in such a cell culture system. First used in embryonic stem cell in vitro culture to recapitulate in vivo developmental processes, 3D spheroid culture has grown in popularity as an in vitro method to mimic the 3-dimensionality of the native niche for MSCs within tissues/organs. In this review, we discuss the relevance of the 3D spheroid culture for understanding MSC biology, summarize the biological outcomes reported in the literature based on such this culture condition, as well as contemplate limitations and future considerations in this rapidly evolving and exciting area.
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Affiliation(s)
- B Linju Yen
- Regenerative Medicine Research Group, Institute of Cellular and System Medicine, National Health Research Institutes (NHRI), Zhunan, Taiwan
| | - Chen-Chan Hsieh
- Regenerative Medicine Research Group, Institute of Cellular and System Medicine, National Health Research Institutes (NHRI), Zhunan, Taiwan
- Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan
| | - Pei-Ju Hsu
- Regenerative Medicine Research Group, Institute of Cellular and System Medicine, National Health Research Institutes (NHRI), Zhunan, Taiwan
| | - Chia-Chi Chang
- Regenerative Medicine Research Group, Institute of Cellular and System Medicine, National Health Research Institutes (NHRI), Zhunan, Taiwan
- Graduate Institute of Life Sciences, National Defense Medical Center (NDMC), Taipei, Taiwan
| | - Li-Tzu Wang
- Department of Obstetrics and Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, Taipei, Taiwan
| | - Men-Luh Yen
- Department of Obstetrics and Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, Taipei, Taiwan
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Murai T, Matsuda S. Pleiotropic Signaling by Reactive Oxygen Species Concerted with Dietary Phytochemicals and Microbial-Derived Metabolites as Potent Therapeutic Regulators of the Tumor Microenvironment. Antioxidants (Basel) 2023; 12:1056. [PMID: 37237922 PMCID: PMC10215163 DOI: 10.3390/antiox12051056] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/02/2023] [Accepted: 05/05/2023] [Indexed: 05/28/2023] Open
Abstract
The excessive generation of reactive oxygen species (ROS) plays a pivotal role in the pathogenesis of diseases. ROS are central to cellular redox regulation and act as second messengers to activate redox-sensitive signals. Recent studies have revealed that certain sources of ROS can be beneficial or harmful to human health. Considering the essential and pleiotropic roles of ROS in basic physiological functions, future therapeutics should be designed to modulate the redox state. Dietary phytochemicals, microbiota, and metabolites derived from them can be expected to be developed as drugs to prevent or treat disorders in the tumor microenvironment.
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Affiliation(s)
- Toshiyuki Murai
- Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita 565-0871, Japan
| | - Satoru Matsuda
- Department of Food Science and Nutrition, Nara Women’s University, Kita-Uoya Nishimachi, Nara 630-8506, Japan
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Nairuz T, Mahmud Z, Manik RK, Kabir Y. Cancer stem cells: an insight into the development of metastatic tumors and therapy resistance. Stem Cell Rev Rep 2023:10.1007/s12015-023-10529-x. [PMID: 37129728 DOI: 10.1007/s12015-023-10529-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/09/2023] [Indexed: 05/03/2023]
Abstract
The term "cancer stem cells" (CSCs) refers to cancer cells that exhibit traits parallel to normal stem cells, namely the potential to give rise to every type of cell identified in a tumor microenvironment. It has been found that CSCs usually develops from other neoplastic cells or non-cancerous somatic cells by acquiring stemness and malignant characteristics through particular genetic modifications. A trivial number of CSCs, identified in solid and liquid cancer, can give rise to an entire tumor population with aggressive anticancer drug resistance, metastasis, and invasiveness. Besides, cancer stem cells manipulate their intrinsic and extrinsic features, regulate the metabolic pattern of the cell, adjust efflux-influx efficiency, modulate different signaling pathways, block apoptotic signals, and cause genetic and epigenetic alterations to retain their pluripotency and ability of self-renewal. Notably, to keep the cancer stem cells' ability to become malignant cells, mesenchymal stem cells, tumor-associated fibroblasts, immune cells, etc., interact with one another. Furthermore, CSCs are characterized by the expression of particular molecular markers that carry significant diagnostic and prognostic significance. Because of this, scientific research on CSCs is becoming increasingly imperative, intending to understand the traits and behavior of cancer stem cells and create more potent anticancer therapeutics to fight cancer at the CSC level. In this review, we aimed to elucidate the critical role of CSCs in the onset and spread of cancer and the characteristics of CSCs that promote severe resistance to targeted therapy.
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Affiliation(s)
- Tahsin Nairuz
- Department of Biochemistry and Molecular Biology, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Zimam Mahmud
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Rasel Khan Manik
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Yearul Kabir
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh.
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Salavaty A, Azadian E, Naik SH, Currie PD. Clonal selection parallels between normal and cancer tissues. Trends Genet 2023; 39:358-380. [PMID: 36842901 DOI: 10.1016/j.tig.2023.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 01/12/2023] [Accepted: 01/26/2023] [Indexed: 02/28/2023]
Abstract
Clonal selection and drift drive both normal tissue and cancer development. However, the biological mechanisms and environmental conditions underpinning these processes remain to be elucidated. Clonal selection models are centered in Darwinian evolutionary theory, where some clones with the fittest features are selected and populate the tissue or tumor. We suggest that different subclasses of stem cells, each of which is responsible for a distinct feature of the selection process, share common features between normal and cancer conditions. While active stem cells populate the tissue, dormant cells account for tissue replenishment/regeneration in both normal and cancerous tissues. We also discuss potential mechanisms that drive clonal drift, their interactions with clonal selection, and their similarities during normal and cancer tissue development.
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Affiliation(s)
- Adrian Salavaty
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia; Systems Biology Institute Australia, Monash University, Clayton, VIC 3800, Australia.
| | - Esmaeel Azadian
- Immunology Division, Walter and Eliza Hall Institute, Parkville, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia
| | - Shalin H Naik
- Immunology Division, Walter and Eliza Hall Institute, Parkville, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia
| | - Peter D Currie
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia; EMBL Australia, Monash University, Clayton, VIC 3800, Australia.
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Tavakoli S, Garcia V, Gähwiler E, Adatto I, Rangan A, Messemer KA, Kakhki SA, Yang S, Chan VS, Manning ME, Fotowat H, Zhou Y, Wagers AJ, Zon LI. Transplantation-based screen identifies inducers of muscle progenitor cell engraftment across vertebrate species. Cell Rep 2023; 42:112365. [PMID: 37018075 PMCID: PMC10548355 DOI: 10.1016/j.celrep.2023.112365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 01/06/2023] [Accepted: 03/22/2023] [Indexed: 04/06/2023] Open
Abstract
Stem cell transplantation presents a potentially curative strategy for genetic disorders of skeletal muscle, but this approach is limited by the deleterious effects of cell expansion in vitro and consequent poor engraftment efficiency. In an effort to overcome this limitation, we sought to identify molecular signals that enhance the myogenic activity of cultured muscle progenitors. Here, we report the development and application of a cross-species small-molecule screening platform employing zebrafish and mice, which enables rapid, direct evaluation of the effects of chemical compounds on the engraftment of transplanted muscle precursor cells. Using this system, we screened a library of bioactive lipids to discriminate those that could increase myogenic engraftment in vivo in zebrafish and mice. This effort identified two lipids, lysophosphatidic acid and niflumic acid, both linked to the activation of intracellular calcium-ion flux, which showed conserved, dose-dependent, and synergistic effects in promoting muscle engraftment across these vertebrate species.
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Affiliation(s)
- Sahar Tavakoli
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA
| | - Vivian Garcia
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA 02138, USA
| | - Eric Gähwiler
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Institute for Regenerative Medicine, University of Zurich, ETH Zurich, Zurich, Switzerland
| | - Isaac Adatto
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA
| | - Apoorva Rangan
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Stanford Medicine, Stanford University, Stanford, CA 94305, USA
| | - Kathleen A Messemer
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA 02138, USA
| | - Sara Ashrafi Kakhki
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA 02138, USA
| | - Song Yang
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA
| | - Victoria S Chan
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA
| | - Margot E Manning
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA
| | - Haleh Fotowat
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
| | - Yi Zhou
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA
| | - Amy J Wagers
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA; Joslin Diabetes Center, Boston, MA 02215, USA.
| | - Leonard I Zon
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA; Children's Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
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50
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Abstract
Over the past decade, melanoma has led the field in new cancer treatments, with impressive gains in on-treatment survival but more modest improvements in overall survival. Melanoma presents heterogeneity and transcriptional plasticity that recapitulates distinct melanocyte developmental states and phenotypes, allowing it to adapt to and eventually escape even the most advanced treatments. Despite remarkable advances in our understanding of melanoma biology and genetics, the melanoma cell of origin is still fiercely debated because both melanocyte stem cells and mature melanocytes can be transformed. Animal models and high-throughput single-cell sequencing approaches have opened new opportunities to address this question. Here, we discuss the melanocytic journey from the neural crest, where they emerge as melanoblasts, to the fully mature pigmented melanocytes resident in several tissues. We describe a new understanding of melanocyte biology and the different melanocyte subpopulations and microenvironments they inhabit, and how this provides unique insights into melanoma initiation and progression. We highlight recent findings on melanoma heterogeneity and transcriptional plasticity and their implications for exciting new research areas and treatment opportunities. The lessons from melanocyte biology reveal how cells that are present to protect us from the damaging effects of ultraviolet radiation reach back to their origins to become a potentially deadly cancer.
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Affiliation(s)
- Patricia P Centeno
- Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, UK
| | - Valeria Pavet
- Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, UK
| | - Richard Marais
- Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, UK.
- Oncodrug Ltd, Alderly Park, Macclesfield, UK.
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