Proteomics

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Fat1 deletion promotes hybrid EMT state, tumor stemness, and metastasis


ABSTRACT: FAT1, a protocadherin, is among 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. In the present study we used different mouse cancer models including skin squamous cell carcinoma (SCC) and lung tumours we found that Fat1 deletion accelerated tumour initiation and malignant progression and promoted hybrid epithelial to mesenchymal transition (EMT) phenotype. This hybrid EMT state was also found in FAT1 mutated human SCCs. Fat1 deleted skin SCCs presented increased tumour stemness and spontaneous metastasis. Transcriptional and chromatin profiling revealed that Yap1 and Sox2 are involved in promoting and stabilizing hybrid EMT state. To unravel the molecular mechanisms by which FAT1 (a protein located on the plasma membrane), lead to the transcriptional changes, we performed phosphor-proteomic analysis of A388 FAT1 WT human SCC cell lines and A388 FAR1 CRISPR KO. This analysis revealed that FAT1 loss of function activates a CAMK2/CD44/SRC axis that promotes YAP/ZEB1 nuclear translocation and stimulates the mesenchymal state, as well as a CAMK2-EZH2 axis that promotes activation of SOX2, which sustains the epithelial state. This comprehensive analysis also identified drug resistance and vulnerabilities in FAT1 deficient tumours with important implications for cancer therapy. Altogether, our studies revealed that Fat1 loss of function promotes tumour initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skin

SUBMITTER: Delphi Van Haver  

LAB HEAD: Cedric Blanpain

PROVIDER: PXD022268 | Pride | 2021-01-18

REPOSITORIES: Pride

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Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis.

Pastushenko Ievgenia I   Mauri Federico F   Song Yura Y   de Cock Florian F   Meeusen Bob B   Swedlund Benjamin B   Impens Francis F   Van Haver Delphi D   Opitz Matthieu M   Thery Manuel M   Bareche Yacine Y   Lapouge Gaelle G   Vermeersch Marjorie M   Van Eycke Yves-Rémi YR   Balsat Cédric C   Decaestecker Christine C   Sokolow Youri Y   Hassid Sergio S   Perez-Bustillo Alicia A   Agreda-Moreno Beatriz B   Rios-Buceta Luis L   Jaen Pedro P   Redondo Pedro P   Sieira-Gil Ramon R   Millan-Cayetano Jose F JF   Sanmatrtin Onofre O   D'Haene Nicky N   Moers Virginie V   Rozzi Milena M   Blondeau Jeremy J   Lemaire Sophie S   Scozzaro Samuel S   Janssens Veerle V   De Troya Magdalena M   Dubois Christine C   Pérez-Morga David D   Salmon Isabelle I   Sotiriou Christos C   Helmbacher Francoise F   Blanpain Cédric C  

Nature 20201216 7842


FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers<sup>1-5</sup>. 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  ...[more]

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