TGF-β orchestrates fibrogenic and developmental EMTs via the RAS effector RREB1

Jie Su, Sophie M. Morgani, Charles J. David, Qiong Wang, Ekrem Emrah Er, Yun-Han Huang, Harihar Basnet, Yilong Zou, Weiping Shu, Rajesh K. Soni, Ronald C. Hendrickson, Anna-Katerina Hadjantonakis and Joan Massagué ()
Additional contact information
Jie Su: Memorial Sloan Kettering Cancer Center
Sophie M. Morgani: Memorial Sloan Kettering Cancer Center
Charles J. David: Memorial Sloan Kettering Cancer Center
Qiong Wang: Memorial Sloan Kettering Cancer Center
Ekrem Emrah Er: Memorial Sloan Kettering Cancer Center
Yun-Han Huang: Memorial Sloan Kettering Cancer Center
Harihar Basnet: Memorial Sloan Kettering Cancer Center
Yilong Zou: Memorial Sloan Kettering Cancer Center
Weiping Shu: Memorial Sloan Kettering Cancer Center
Rajesh K. Soni: Memorial Sloan Kettering Cancer Center
Ronald C. Hendrickson: Memorial Sloan Kettering Cancer Center
Anna-Katerina Hadjantonakis: Memorial Sloan Kettering Cancer Center
Joan Massagué: Memorial Sloan Kettering Cancer Center

Nature, 2020, vol. 577, issue 7791, 566-571

Abstract: Abstract Epithelial-to-mesenchymal transitions (EMTs) are phenotypic plasticity processes that confer migratory and invasive properties to epithelial cells during development, wound-healing, fibrosis and cancer1–4. EMTs are driven by SNAIL, ZEB and TWIST transcription factors5,6 together with microRNAs that balance this regulatory network7,8. Transforming growth factor β (TGF-β) is a potent inducer of developmental and fibrogenic EMTs4,9,10. Aberrant TGF-β signalling and EMT are implicated in the pathogenesis of renal fibrosis, alcoholic liver disease, non-alcoholic steatohepatitis, pulmonary fibrosis and cancer4,11. TGF-β depends on RAS and mitogen-activated protein kinase (MAPK) pathway inputs for the induction of EMTs12–19. 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 effector20,21, 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.

Date: 2020
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DOI: 10.1038/s41586-019-1897-5

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