TGF-β and RREB1 coordinate EMT programs in development and cancer. TGF-β and RREB1 coordinate EMT programs in development and cancer

Epithelial-to-mesenchymal transitions (EMT) play prominent roles during development, regeneration and tumor progression. EMTs are triggered by TGF-β, RAS and other signals that cooperatively induce the expression of master EMT transcription factors such as SNAIL. Here, we elucidate how the TGF-β and RAS pathways jointly trigger EMTs and tie them to broader developmental programs. We identify RAS response element binding protein 1 (RREB1) as a critical partner of TGF-β-activated SMAD transcription factors in driving SNAIL expression in pancreatic pre-malignant epithelial cells, lung adenocarcinoma cells, and embryonic stem cells. Moreover, SMADs and RREB1 also drive EMT-associated fibrogenic programs in epithelial cells and mesendoderm differentiation in pluripotent embryonic cells. These findings illuminate the orchestration of EMT associated programs in gastrulation, fibrosis, and cancer. Overall design: RNA-seq, ChIP-seq, and ATAC-seq are used to profile pancreatic organoid, pancreatic adenocarcinoma cells, and embryonic stem cells

上皮间质转化（Epithelial-to-mesenchymal transitions, EMT）在发育、组织再生与肿瘤进展过程中发挥关键调控作用。上皮间质转化可由转化生长因子β（Transforming Growth Factor-β, TGF-β）、RAS等信号通路触发，这些信号可协同诱导上皮间质转化核心转录因子（如SNAIL）的表达。本研究阐明了转化生长因子β与RAS信号通路如何协同触发上皮间质转化，并将该过程与更广泛的发育程序建立关联。我们鉴定出RAS应答元件结合蛋白1（RAS response element binding protein 1, RREB1）为转化生长因子β激活的SMAD转录因子的关键协同伴侣，可在胰腺癌前上皮细胞、肺腺癌细胞与胚胎干细胞中介导SNAIL的表达。此外，SMAD蛋白与RREB1还可在上皮细胞中调控上皮间质转化相关的纤维化程序，并在多能胚胎细胞中促进中内胚层分化。本研究结果揭示了上皮间质转化相关程序在原肠胚形成、纤维化及癌症发生中的调控机制。实验设计概述：本研究采用RNA测序（RNA-seq）、染色质免疫沉淀测序（ChIP-seq）以及转座酶可及性测序（ATAC-seq），对胰腺类器官、胰腺腺癌细胞与胚胎干细胞进行组学特征分析。