دورية أكاديمية
Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis
| العنوان: | Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis |
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| المؤلفون: | Pastushenko, Ievgenia, Mauri, Federico, Song, Yura, de Cock, Florian, Meeusen, Bob, Swedlund, Benjamin, Impens, Francis, van Haver, Delphi, Opitz, Matthieu, Thery, Manuel, Bareche, Yacine, Lapouge, Gaelle, Vermeersch, Marjorie, van Eycke, Yves-Rémi, Balsat, Cédric, Decaestecker, Christine, Sokolow, Youri, Hassid, Sergio, Perez-Bustillo, Alicia, Agreda-Moreno, Beatriz, Rios-Buceta, Luis, Jaen, Pedro, Redondo, Pedro, Sieira-Gil, Ramon, Millan-Cayetano, Jose, Sanmatrtin, Onofre, D’haene, Nicky, Moers, Virginie, Rozzi, Milena, Blondeau, Jeremy, Lemaire, Sophie, Scozzaro, Samuel, Janssens, Veerle, de Troya, Magdalena, Dubois, Christine, Pérez-Morga, David, Salmon, Isabelle, Sotiriou, Christos, Helmbacher, Françoise, Blanpain, Cédric |
| المساهمون: | Université libre de Bruxelles (ULB), Dermatology Department, Cliniques de l'Europe, Brussels, Belgium, Catholic University of Leuven = Katholieke Universiteit Leuven (KU Leuven), Leuven Cancer Institute (LKI), Leuven, Belgium, VIB-UGent Center for Medical Biotechnology, VIB Proteomics Core, Ghent, Belgium, Universiteit Gent = Ghent University (UGENT), VIB proteomic core, Ghent, Belgium, Alvéole, Paris, France., CytoMorphoLab, Chimie-Biologie-Innovation (UMR 8231) (CBI), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Physiologie cellulaire et végétale (LPCV), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Ecole Polytechnique de Bruxelles, Department of Dermatology, Complejo Asistencial Universitario de León, León, Spain, Department of Otolaryngology - Head and Neck Surgery, Hospital Clinico 'Lozano Blesa', Zaragoza, Spain, Dermatology Department, Ramón y Cajal Hospital, Madrid, Spain, University of Alcalá, Madrid, Spain, Instituto Ramon y Cajal de Investigacion Sanitaria Madrid, Spain (IRYCIS), Universidad de Alcalá - University of Alcalá (UAH), Department of Dermatology, Clinica Universidad de Navarra, Navarra, Spain, Department of Maxillofacial Surgery, Head and Neck Surgery, Hospital Clínic, Barcelona, Spain, Department of Dermatology, Hospital Costa del Sol, Marbella, Spain, Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Walloon excellence in life sciences and biotechnology (WELBIO), Fonds de la Recherche Scientifique (FNRS), European Regional Development Fund, Walloon Region, Televie (Charity Association), European Research Council, Fond Erasme, Fondation Contre le Cancer, ULB Foundation, Worldwide Cancer Research, Foundation Baillet Latour |
| المصدر: | ISSN: 0028-0836. |
| بيانات النشر: | HAL CCSD Nature Publishing Group |
| سنة النشر: | 2021 |
| المجموعة: | Université Grenoble Alpes: HAL |
| مصطلحات موضوعية: | [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer |
| الوصف: | International audience ; FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers. However, the role and the molecular mechanisms by which FAT1 mutations control tumour initiation and progression are poorly understood. Here, using mouse models of skin squamous cell carcinoma and lung tumours, we found that deletion of Fat1 accelerates tumour initiation and malignant progression and promotes a hybrid epithelial-to-mesenchymal transition (EMT) phenotype. We also found this hybrid EMT state in FAT1-mutated human squamous cell carcinomas. Skin squamous cell carcinomas in which Fat1 was deleted presented increased tumour stemness and spontaneous metastasis. We performed transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies, which revealed that loss of function of FAT1 activates a CAMK2-CD44-SRC axis that promotes YAP1 nuclear translocation and ZEB1 expression that stimulates the mesenchymal state. This loss of function also inactivates EZH2, promoting SOX2 expression, which sustains the epithelial state. Our comprehensive analysis identified drug resistance and vulnerabilities in FAT1-deficient tumours, which have important implications for cancer therapy. Our studies reveal that, in mouse and human squamous cell carcinoma, loss of function of FAT1 promotes tumour initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/33328637; hal-03081403; https://hal.science/hal-03081403Test; https://hal.science/hal-03081403/documentTest; https://hal.science/hal-03081403/file/Pastushenko%20et%20al%20Full%20text.pdfTest; PUBMED: 33328637 |
| DOI: | 10.1038/s41586-020-03046-1 |
| الإتاحة: | https://doi.org/10.1038/s41586-020-03046-1Test https://hal.science/hal-03081403Test https://hal.science/hal-03081403/documentTest https://hal.science/hal-03081403/file/Pastushenko%20et%20al%20Full%20text.pdfTest |
| حقوق: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.A103AD04 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41586-020-03046-1 |
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