RESUMO
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.
Assuntos
Caderinas/deficiência , Transição Epitelial-Mesenquimal/genética , Deleção de Genes , Metástase Neoplásica/genética , Neoplasias/genética , Neoplasias/patologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Caderinas/genética , Caderinas/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Progressão da Doença , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Receptores de Hialuronatos/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mesoderma/metabolismo , Mesoderma/patologia , Camundongos , Metástase Neoplásica/tratamento farmacológico , Neoplasias/tratamento farmacológico , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fenótipo , Fosfoproteínas/análise , Fosfoproteínas/metabolismo , Proteômica , Fatores de Transcrição SOXB1/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAP , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Quinases da Família src/metabolismoRESUMO
Una fístula oroantral es una solución de continuidad patológica entre el seno maxilar y la cavidad oral, producida frecuentemente tras una extracción dentaria, en la mayoría de los casos, del primer o segundo molar. El síntoma más común que provoca es una sinusitis aguda, que evolucionará a la cronicidad si la fístula permanece. El diagnóstico se realiza mediante endoscopia transalveolar, ortopantografía o tomografía computarizada dental. Su cierre quirúrgico es necesario cuando la fístula tiene más de 3 mm, o no sella por sí misma en 3 semanas. Existen, para ello, varias técnicas, usando distintos materiales y colgajos, cuyo fin es ocluir, tanto el defecto óseo, como el mucoso, para solucionar así a la vez la fístula y el problema sinusal(AU)
The oroantral fistula is a solution of pathological continuity between the maxillary sinus and the oral cavity, frequently produced after a teeth extraction in most of cases of the first or second molars. The commonest symptom provoked is an acute sinusitis evolving to chronicity if the fistula remains. The diagnosis is made by transalveolar, orthopantography or dental computerized tomography. Its surgical closure is necessary when the fistula has more than 3 mm or not seal by itself in three weeks. For it, there are some techniques using different materials and flaps where its objective is to occlude the bone defect as well as the mucous one thus solving the fistula and the sinus problem(AU)