1. Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis.
- Author
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Pastushenko I, Mauri F, Song Y, de Cock F, Meeusen B, Swedlund B, Impens F, Van Haver D, Opitz M, Thery M, Bareche Y, Lapouge G, Vermeersch M, Van Eycke YR, Balsat C, Decaestecker C, Sokolow Y, Hassid S, Perez-Bustillo A, Agreda-Moreno B, Rios-Buceta L, Jaen P, Redondo P, Sieira-Gil R, Millan-Cayetano JF, Sanmatrtin O, D'Haene N, Moers V, Rozzi M, Blondeau J, Lemaire S, Scozzaro S, Janssens V, De Troya M, Dubois C, Pérez-Morga D, Salmon I, Sotiriou C, Helmbacher F, and Blanpain C
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Animals, Cadherins genetics, Cadherins metabolism, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell pathology, Disease Progression, Enhancer of Zeste Homolog 2 Protein metabolism, Epithelial Cells metabolism, Epithelial Cells pathology, Epithelial-Mesenchymal Transition drug effects, Gene Expression Regulation, Neoplastic, Humans, Hyaluronan Receptors metabolism, Lung Neoplasms genetics, Lung Neoplasms pathology, Mesoderm metabolism, Mesoderm pathology, Mice, Neoplasm Metastasis drug therapy, Neoplasms drug therapy, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Phenotype, Phosphoproteins analysis, Phosphoproteins metabolism, Proteomics, SOXB1 Transcription Factors metabolism, Signal Transduction, Skin Neoplasms genetics, Skin Neoplasms pathology, Transcription Factors metabolism, YAP-Signaling Proteins, Zinc Finger E-box-Binding Homeobox 1 metabolism, src-Family Kinases metabolism, Cadherins deficiency, Epithelial-Mesenchymal Transition genetics, Gene Deletion, Neoplasm Metastasis genetics, Neoplasms genetics, Neoplasms pathology
- Abstract
FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers
1-5 . 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.- Published
- 2021
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