000102099 001__ 102099 000102099 005__ 20210902121937.0 000102099 0247_ $$2doi$$a10.1038/s41586-020-03046-1 000102099 0248_ $$2sideral$$a122559 000102099 037__ $$aART-2020-122559 000102099 041__ $$aeng 000102099 100__ $$aPastushenko, I. 000102099 245__ $$aFat1 deletion promotes hybrid EMT state, tumour stemness and metastasis 000102099 260__ $$c2020 000102099 5060_ $$aAccess copy available to the general public$$fUnrestricted 000102099 5203_ $$aFAT1, 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. 000102099 540__ $$9info:eu-repo/semantics/openAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/ 000102099 590__ $$a49.962$$b2020 000102099 591__ $$aMULTIDISCIPLINARY SCIENCES$$b1 / 73 = 0.014$$c2020$$dQ1$$eT1 000102099 592__ $$a15.993$$b2020 000102099 593__ $$aMultidisciplinary$$c2020$$dQ1 000102099 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/acceptedVersion 000102099 700__ $$aMauri, F. 000102099 700__ $$aSong, Y. 000102099 700__ $$ade Cock, F. 000102099 700__ $$aMeeusen, B. 000102099 700__ $$aSwedlund, B. 000102099 700__ $$aImpens, F. 000102099 700__ $$aVan Haver, D. 000102099 700__ $$aOpitz, M. 000102099 700__ $$aThery, M. 000102099 700__ $$aBareche, Y. 000102099 700__ $$aLapouge, G. 000102099 700__ $$aVermeersch, M. 000102099 700__ $$aVan Eycke, Y.R. 000102099 700__ $$aBalsat, C. 000102099 700__ $$aDecaestecker, C. 000102099 700__ $$aSokolow, Y. 000102099 700__ $$aHassid, S. 000102099 700__ $$aPerez-Bustillo, A. 000102099 700__ $$aAgreda-Moreno, B. 000102099 700__ $$aRios-Buceta, L. 000102099 700__ $$aJaen, P. 000102099 700__ $$aRedondo, P. 000102099 700__ $$aSieira-Gil, R. 000102099 700__ $$aMillan-Cayetano, J.F. 000102099 700__ $$aSanmatrtin, O. 000102099 700__ $$aD’Haene, N. 000102099 700__ $$aMoers, V. 000102099 700__ $$aRozzi, M. 000102099 700__ $$aBlondeau, J. 000102099 700__ $$aLemaire, S. 000102099 700__ $$aScozzaro, S. 000102099 700__ $$aJanssens, V. 000102099 700__ $$aDe Troya, M. 000102099 700__ $$aDubois, C. 000102099 700__ $$aPérez-Morga, D. 000102099 700__ $$aSalmon, I. 000102099 700__ $$aSotiriou, C. 000102099 700__ $$aHelmbacher, F. 000102099 700__ $$aBlanpain, C. 000102099 773__ $$g589 (2020), 448-455$$pNature$$tNature$$x0028-0836 000102099 8564_ $$s2564279$$uhttps://zaguan.unizar.es/record/102099/files/texto_completo.pdf$$yPostprint 000102099 8564_ $$s3013305$$uhttps://zaguan.unizar.es/record/102099/files/texto_completo.jpg?subformat=icon$$xicon$$yPostprint 000102099 909CO $$ooai:zaguan.unizar.es:102099$$particulos$$pdriver 000102099 951__ $$a2021-09-02-10:58:57 000102099 980__ $$aARTICLE