Sanchez Tillo, E.Pedrosa, LeireVila, I.Chen, YaoGyorffy, B.Sánchez Moral, L.Siles Mena, LauraLozano Salvatella, Juan JoséEsteve Codina, A.Darling, Douglas S.Cuatrecasas Freixas, MiriamCastells Garangou, AntoniMaurel Santasusana, JoanPostigo, Antonio2024-03-132024-03-132023-10-232379-3708https://hdl.handle.net/2445/208724Despite 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.19 p.application/pdfengcc by (c) Sánchez Tilló, Ester et al., 2023http://creativecommons.org/licenses/by/3.0/es/CàncerTransducció de senyal cel·lularCarcinomaSignal Transductioninfo:eu-repo/semantics/article2024-03-05info:eu-repo/semantics/openAccess937986637870961