Epithelial-to-mesenchymal transitions (EMTs) are phenotypic plasticity processes that confer migratory and invasive properties to epithelial cells during development, wound-healing, fibrosis and cancer^1,2,3,4. EMTs are driven by SNAIL, ZEB and TWIST transcription factors^5,6 together with microRNAs that balance this regulatory network^7,8. Transforming growth factor β (TGF-β) is a potent inducer of developmental and fibrogenic EMTs^4,9,10. Aberrant TGF-β signalling and EMT are implicated in the pathogenesis of renal fibrosis, alcoholic liver disease, non-alcoholic steatohepatitis, pulmonary fibrosis and cancer^4,11. TGF-β depends on RAS and mitogen-activated protein kinase (MAPK) pathway inputs for the induction of EMTs^{12,13,14,15,16,17,18,19}. Here we show how these signals coordinately trigger EMTs and integrate them with broader pathophysiological processes. We identify RAS-responsive element binding protein 1 (RREB1), a RAS transcriptional effector^20,21, as a key partner of TGF-β-activated SMAD transcription factors in EMT. MAPK-activated RREB1 recruits TGF-β-activated SMAD factors to SNAIL. Context-dependent chromatin accessibility dictates the ability of RREB1 and SMAD to activate additional genes that determine the nature of the resulting EMT. In carcinoma cells, TGF-β–SMAD and RREB1 directly drive expression of SNAIL and fibrogenic factors stimulating myofibroblasts, promoting intratumoral fibrosis and supporting tumour growth. In mouse epiblast progenitors, Nodal–SMAD and RREB1 combine to induce expression of SNAIL and mesendoderm-differentiation genes that drive gastrulation. Thus, RREB1 provides a molecular link between RAS and TGF-β pathways for coordinated induction of developmental and fibrogenic EMTs. These insights increase our understanding of the regulation of epithelial plasticity and its pathophysiological consequences in development, fibrosis and cancer.

^{上皮-间质转化 (EMT) 是表型可塑性过程，在发育、伤口愈合、纤维化和癌症1,2,3,4}期间赋予上皮细胞迁移和侵袭特性。EMT 由 SNAIL、ZEB 和 TWIST 转录因子^5,6以及平衡此监管网络^7,8的 microRNA 驱动。转化生长因子 β (TGF-β) 是发育和纤维化 EMT 的有效诱导剂^4,9,10。异常的 TGF-β 信号传导和 EMT 与肾纤维化、酒精性肝病、非酒精性脂肪性肝炎、肺纤维化和癌症的发病机制有关^4,11. TGF-β 依赖于 RAS 和丝裂原活化蛋白激酶 (MAPK) 通路输入来诱导 EMT ^{12,13,14,15,16,17,18,19}。在这里，我们展示了这些信号如何协调触发 EMT 并将它们与更广泛的病理生理过程相结合。我们确定 RAS 反应元件结合蛋白 1 (RREB1)，一种 RAS 转录效应子^20,21，作为 EMT 中 TGF-β 激活的 SMAD 转录因子的关键伙伴。MAPK 激活的 RREB1 将 TGF-β 激活的 SMAD 因子招募到SNAIL. 上下文相关的染色质可及性决定了 RREB1 和 SMAD 激活其他基因的能力，这些基因决定了 EMT 的性质。在癌细胞中，TGF-β-SMAD 和 RREB1 直接驱动 SNAIL 和纤维化因子的表达，刺激肌成纤维细胞，促进肿瘤内纤维化并支持肿瘤生长。在小鼠外胚层祖细胞中，Nodal-SMAD 和 RREB1 结合诱导 SNAIL 和驱动原肠胚形成的中内胚层分化基因的表达。因此，RREB1 提供了 RAS 和 TGF-β 途径之间的分子联系，用于协调诱导发育和纤维化 EMT。这些见解增加了我们对上皮可塑性调节及其在发育、纤维化和癌症中的病理生理学后果的理解。