Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis

Abstract

FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers [1][2][3][4][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.

Epithelial–Mesenchymal Transition in Liver Fluke-Induced Cholangiocarcinoma

“…Interestingly, two liver-fluke associated CCA cell lines with differential epithelial and mesenchymal characteristics also exhibited differential metastatic capacities in animal models [31]. This is in agreement with the emerging consensus on cancer EMT, supported by data from many cancer models, pointing an association between a tumor cell's partial EMT features and its metastatic malignancy [40,41]. Finally, consistent with these findings, O. viverrini is known to secrete granulin [32,33] and glutathione S-transferase [35], both known as potent mitogens and EMT inducers [34][35][36]42].…”

Resveratrol and Its Analogs: Potent Agents to Reverse Epithelial-to-Mesenchymal Transition in Tumors

“…EMT is an evolutionarily conserved process whereby epithelial cells lose cell junctions and apical-basal polarity, and are eventually converted into migratory mesenchymal phenotype (64). As a key program, EMT participates in the development of embryogenesis such as gastrulation and tissue morphogenesis, as well as wound healing of adult (65).…”

Interconnected High-Dimensional Landscapes of Epithelial-Mesenchymal Plasticity and Stemness

“…Recent findings in squamous cell carcinoma (SCC) have shed new light on EMP, and its association with stemness. Using a DMBA/TPA induced mouse model of cutaneous SCC, Pastushenko and colleagues demonstrated that FAT1 loss causes the appearance of a hybrid E/M cell state that co-expresses both epithelial and mesenchymal markers [86]. This state was associated with increased metastasis.…”

“…The authors elaborated on this mechanism by showing that FAT1 loss acts through two separate signalling pathways; CAMK2-CD44-SRC-YAP-ZEB1 activates a mesenchymal program, and CAMK2-EZH2-SOX2 activates an epithelial program [86]. Therefore, the hybrid state is induced through a balance of epithelial and mesenchymal signals.…”