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. In mouse and human squamous cell carcinoma, loss of function of FAT1 promotes tumour initiation, malignant progression and metastasis through the activation of a hybrid epithelial-to-mesenchymal transition phenotype.

中文翻译：

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Fat1 缺失促进混合 EMT 状态、肿瘤干性和转移

FAT1 编码一种原钙粘蛋白，是人类癌症中最常发生突变的基因之一 1 – 5 。然而，人们对 FAT1 突变控制肿瘤起始和进展的作用和分子机制知之甚少。在这里，使用皮肤鳞状细胞癌和肺肿瘤的小鼠模型，我们发现 Fat1 的缺失加速了肿瘤的发生和恶性进展，并促进了混合上皮-间质转化 (EMT) 表型。我们还在 FAT1 突变的人类鳞状细胞癌中发现了这种混合 EMT 状态。缺失 Fat1 的皮肤鳞状细胞癌表现出增加的肿瘤干性和自发转移。我们结合蛋白质组学分析和机制研究进行了转录和染色质分析，这表明 FAT1 的功能丧失激活了促进 YAP1 核转位和刺激间充质状态的 ZEB1 表达的 CAMK2-CD44-SRC 轴。这种功能丧失也会使 EZH2 失活，促进 SOX2 表达，从而维持上皮状态。我们的综合分析确定了 FAT1 缺陷型肿瘤的耐药性和脆弱性，这对癌症治疗具有重要意义。我们的研究表明，在小鼠和人类鳞状细胞癌中，FAT1 功能的丧失通过诱导混合 EMT 状态促进肿瘤的发生、进展、侵袭性、干性和转移。在小鼠和人类鳞状细胞癌中，FAT1 功能丧失促进肿瘤发生，