比利时布鲁塞尔自由大学（ULB）Cdric Blanpain团队取得一项新突破。他们的研究发现Fat1删除促进混合上皮-间充质转化（EMT）状态、肿瘤干性和转移。这一研究成果发表在2020年12月16日的《自然》杂志上。
使用皮肤鳞状细胞癌和肺肿瘤的小鼠模型，他们发现Fat1的缺失会加速肿瘤的发生和恶性进展，并促进混合EMT表型。他们还在FAT1突变的人类鳞状细胞癌中发现了这种混合EMT状态。Fat1缺失的皮肤鳞状细胞癌表现出增加的肿瘤干性和自发转移。
他们结合蛋白质组学分析和机理研究进行了转录和染色质分析，结果表明FAT1功能的丧失激活了CAMK2-CD44-SRC轴，从而促进了YAP1核易位和ZEB1表达，从而刺激了间充质状态。这种功能丧失还使EZH2失活，从而促进SOX2表达，从而维持上皮状态。综合分析确定了FAT1缺乏肿瘤的耐药性和脆弱性，这对癌症治疗具有重要意义。
他们的研究表明，在小鼠和人类鳞状细胞癌中，FAT1功能的丧失会通过诱导混合EMT状态促进肿瘤的发生、进展、侵袭性、干性和转移。
据悉，FAT1编码一种原钙粘蛋白，是人类癌症中最常见的突变基因之一。但是，人们尚不清楚FAT1突变控制肿瘤的发生和发展的作用和分子机制。
附：英文原文
Title: Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis
Author: Ievgenia Pastushenko, Federico Mauri, Yura Song, Florian de Cock, Bob Meeusen, Benjamin Swedlund, Francis Impens, Delphi Van Haver, Matthieu Opitz, Manuel Thery, Yacine Bareche, Gaelle Lapouge, Marjorie Vermeersch, Yves-Rmi Van Eycke, Cdric Balsat, Christine Decaestecker, Youri Sokolow, Sergio Hassid, Alicia Perez-Bustillo, Beatriz Agreda-Moreno, Luis Rios-Buceta, Pedro Jaen, Pedro Redondo, Ramon Sieira-Gil, Jose F. Millan-Cayetano, Onofre Sanmatrtin, Nicky DHaene, Virginie Moers, Milena Rozzi, Jeremy Blondeau, Sophie Lemaire, Samuel Scozzaro, Veerle Janssens, Magdalena De Troya, Christine Dubois, David Prez-Morga, Isabelle Salmon, Christos Sotiriou, Francoise Helmbacher, Cdric Blanpain
Issue&Volume: 2020-12-16
Abstract: FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers1,2,3,4,5. 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.
DOI: 10.1038/s41586-020-03046-1
Source: https://www.nature.com/articles/s41586-020-03046-1
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
