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.
Subject(s)
Cadherins/deficiency , Epithelial-Mesenchymal Transition/genetics , Gene Deletion , Neoplasm Metastasis/genetics , Neoplasms/genetics , Neoplasms/pathology , 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/metabolismABSTRACT
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Subject(s)
Humans , Female , Middle Aged , Plasmacytoma/diagnosis , Frontal Sinus/pathology , Paranasal Sinus Neoplasms/surgery , Diagnosis, Differential , Tomography, X-Ray ComputedABSTRACT
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)
