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The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas
Ester Sánchez-Tilló1,2,3, Leire Pedrosa4, Ingrid Vila1
1Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Department of Oncology and Hematology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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.
Insights
ZEB1 has opposing roles in colorectal cancer progression based on KRAS or BRAF mutations. In KRAS-mutant tumors, ZEB1 worsens prognosis, while in BRAF-mutant tumors, it improves outcomes and reduces metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Colorectal carcinomas (CRCs) with KRAS and BRAF mutations exhibit different progression patterns.
- ZEB1 is known to induce epithelial-to-mesenchymal transition (EMT) and is often linked to poor prognosis in various cancers.
Purpose of the Study:
- To investigate the contrasting functions of ZEB1 in KRAS-mutant versus BRAF-mutant colorectal cancer.
- To elucidate the mechanistic basis for ZEB1's differential impact on tumor progression and metastasis.
Main Methods:
- Analysis of patient CRC samples and KrasG12D/BrafV600E mouse models.
- Utilized Zeb1-deficient mice for functional studies.
- Assessed gene expression signatures for EMT, proliferation, survival, and ERK signaling.
- Performed ZEB1 knockdown experiments to evaluate cellular phenotypes.
Main Results:
- ZEB1 correlated with worse prognosis and increased EMT in KRAS-mutant CRCs.
- ZEB1 was associated with better prognosis, reduced EMT, and fewer metastases in BRAF-mutant CRCs.
- ZEB1 showed opposing correlations with EMT, proliferation, survival, and ERK signaling gene signatures in KRAS- vs. BRAF-mutant CRC cells.
Conclusions:
- ZEB1 exhibits context-dependent roles in CRC, acting as an oncogene in KRAS-mutant tumors and a tumor suppressor in BRAF-mutant tumors.
- These findings underscore the critical importance of the KRAS/BRAF mutational status in CRC when considering ZEB1 or EMT-targeted therapies.
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