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JCI Insight.pdf (20.86 MB)

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2023-10-23

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cc by (c) Sánchez Tilló, Ester et al., 2023
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/208724

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

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https://doi.org/10.1172/jci.insight.164629

Abstract

Despite 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.

Subject

Càncer, Transducció de senyal cel·lular

Subject (English)

Carcinoma, Signal Transduction

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Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

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SANCHEZ TILLO, E., et al. The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas. Jci Insight. 2023. Vol. 8, num. 20, pags. e164629. ISSN 2379-3708. [consulted: 14 of August of 2026]. Available at: https://hdl.handle.net/2445/208724

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