Sánchez-Tilló, EsterPedrosa, LeireVila, IngridChen, YongxuGyorffy, BalázsSánchez-Moral, LidiaSiles, LauraLozano, Juan JoséEsteve-Codina, AnnaDarling, Douglas S.Cuatrecasas, MiriamCastells, AntoniMaurel, JoanPostigo, Antonio2024-02-092024-02-092023Sánchez-Tilló E, Pedrosa L, Vila I, Chen Y, Győrffy B, Sánchez-Moral L, Siles L, Lozano JJ, Esteve-Codina A, Darling DS, Cuatrecasas M, Castells A, Maurel J, Postigo A. The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas. JCI Insight. 2023 Oct 23;8(20):e164629. DOI: 10.1172/jci.insight.1646292379-3708http://hdl.handle.net/10230/59044Despite being in the same pathway, mutations of KRAS and BRAF in colorectal carcinomas (CRCs) determine distinct progression courses. ZEB1 induces an epithelial-to-mesenchymal transition (EMT) and is associated with worse progression in most carcinomas. Using samples from patients with CRC, mouse models of KrasG12D and BrafV600E CRC, and a Zeb1-deficient mouse, we show that ZEB1 had opposite functions in KRAS- and BRAF-mutant CRCs. In KrasG12D CRCs, ZEB1 was correlated with a worse prognosis and a higher number of larger and undifferentiated (mesenchymal or EMT-like) tumors. Surprisingly, in BrafV600E CRC, ZEB1 was associated with better prognosis; fewer, smaller, and more differentiated (reduced EMT) primary tumors; and fewer metastases. ZEB1 was positively correlated in KRAS-mutant CRC cells and negatively in BRAF-mutant CRC cells with gene signatures for EMT, cell proliferation and survival, and ERK signaling. On a mechanistic level, ZEB1 knockdown in KRAS-mutant CRC cells increased apoptosis and reduced clonogenicity and anchorage-independent growth; the reverse occurred in BRAFV600E CRC cells. ZEB1 is associated with better prognosis and reduced EMT signature in patients harboring BRAF CRCs. These data suggest that ZEB1 can function as a tumor suppressor in BRAF-mutant CRCs, highlighting the importance of considering the KRAS/BRAF mutational background of CRCs in therapeutic strategies targeting ZEB1/EMT.application/pdfeng© 2023, Sánchez-Tilló et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).info:eu-repo/semantics/articlehttp://dx.doi.org/10.1172/jci.insight.164629Colorectal cancerGastroenterologyOncologyinfo:eu-repo/semantics/openAccess