The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas

• DOI: 10.1172/jci.insight.164629
• Publication Date: 2023-10-22T18:00:48Z
• Authors: Ester Sánchez-Tilló; Leire Pedrosa; Ingrid Vila; Yongxu Chen; Balázs Győrffy; Lidia Sánchez-Moral; Laura Siles; Juan J. Lozano; Anna Esteve-Codina; Douglas S. Darling; Miriam Cuatrecasas; Antoni Castells; Joan Maurel; Antonio Postigo
• Keywords: Proto-Oncogene Proteins B-raf; Carcinoma; Gastroenterology; R; Transducció de senyal cel·lular; Zinc Finger E-box-Binding Homeobox 1; Colorectal cancer; [SDV] Life Sciences [q-bio]; Proto-Oncogene Proteins p21(ras); Mice; Oncology; Medicine; Animals; Humans; Càncer; Colorectal Neoplasms; Research Article; Signal Transduction

Despite being in the same pathway, mutations of KRAS and BRAF colorectal carcinomas (CRCs) determine distinct progression courses. ZEB1 induces an epithelial-to-mesenchymal transition (EMT) is associated with worse most carcinomas. Using samples from patients CRC, mouse models KrasG12D BrafV600E a Zeb1-deficient mouse, we show that had opposite functions KRAS- BRAF-mutant CRCs. In CRCs, was correlated prognosis higher number larger undifferentiated (mesenchymal or EMT-like) tumors. Surprisingly, better prognosis; fewer, smaller, more differentiated (reduced EMT) primary tumors; fewer metastases. positively KRAS-mutant CRC cells negatively gene signatures for EMT, cell proliferation survival, ERK signaling. On mechanistic level, knockdown increased apoptosis reduced clonogenicity anchorage-independent growth; reverse occurred BRAFV600E cells. EMT signature harboring These data suggest can function as tumor suppressor highlighting importance considering KRAS/BRAF mutational background CRCs therapeutic strategies targeting ZEB1/EMT.