1. Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis
- Author
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Françoise Helmbacher, Jose Jf Millan-Cayetano, Ievgenia Pastushenko, L. Ríos-Buceta, Benjamin Swedlund, Alicia Perez-Bustillo, Magdalena De Troya, Delphi Van Haver, Sergio Hassid, Francis Impens, Bob Meeusen, Sophie Lemaire, Yura Song, Christine Decaestecker, Gaëlle Lapouge, Ramon Sieira-Gil, Cédric Balsat, David Perez-Morga, Beatriz Agreda-Moreno, Cédric Blanpain, Pedro Redondo, Matthieu Opitz, Youri Sokolow, Isabelle Salmon, Christos Sotiriou, Onofre Sanmatrtin, Frédérique De Cock, Virginie Moers, Samuel Scozzaro, Marjorie Vermeersch, Pedro Jaén, Yacine Bareche, Christine Dubois, Milena Rozzi, Nicky D'Haene, Manuel Théry, Yves-Remi Van Eycke, Jeremy Blondeau, Veerle Janssens, Federico Mauri, Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels 1070, Belgium., Dermatology Department, Cliniques de l'Europe, Brussels, Belgium, Université libre de Bruxelles (ULB), 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 UMR976 HIPI, CEA, INSERM, Université de Paris, Paris, France, CytoMorphoLab, 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), 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, Pathology Department, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), WELBIO, Université Libre de Bruxelles (ULB), Brussels, Belgium, 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, Helmbacher, Francoise, Dermatology Department, CHU Brugmann, Université Libre de Bruxelles (ULB), Brussels, Belgium, Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium, VIB Center for Medical Biotechnology, Ghent, Belgium, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium, Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium., Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles (ULB), Charleroi, Belgium, DIAPath, Center for Microscopy and Molecular Imaging, Université Libre de Bruxelles (ULB), Charleroi, Belgium, Laboratory of Image Synthesis and Analysis, Ecole Polytechnique de Bruxelles, Université Libre de Bruxelles (ULB), Brussels, Belgium, Department of Thoracic Surgery, Erasme University Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium, Department of Otolaryngology - Head and Neck Surgery, Erasme University Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium, and Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
- Subjects
0301 basic medicine ,Proteomics ,Lung Neoplasms ,Skin Neoplasms ,[SDV]Life Sciences [q-bio] ,Cell ,Metastasis ,Mesoderm ,Mice ,0302 clinical medicine ,Neoplasms ,Neoplasm Metastasis ,YAP1 ,Regulation of gene expression ,Multidisciplinary ,EZH2 ,Cadherins ,3. Good health ,[SDV] Life Sciences [q-bio] ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Hyaluronan Receptors ,Phenotype ,src-Family Kinases ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,Disease Progression ,Neoplastic Stem Cells ,FAT1 ,Signal Transduction ,Epithelial-Mesenchymal Transition ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Article ,03 medical and health sciences ,SOX2 ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,medicine ,Skin Squamous Cell Carcinoma ,Animals ,Humans ,Enhancer of Zeste Homolog 2 Protein ,Adaptor Proteins, Signal Transducing ,SOXB1 Transcription Factors ,Médecine pathologie humaine ,Biologie moléculaire ,Zinc Finger E-box-Binding Homeobox 1 ,Epithelial Cells ,YAP-Signaling Proteins ,medicine.disease ,Phosphoproteins ,Cancérologie ,030104 developmental biology ,Cancer research ,Biologie cellulaire ,Gene Deletion ,Transcription Factors - Abstract
FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers1-5. 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., info:eu-repo/semantics/published
- Published
- 2021
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