An FBXW7-ZEB2 axis links EMT and tumour microenvironment to promote colorectal cancer stem cells and chemoresistance

Ningning Li, Roya Babaei-Jadidi, Federica Lorenzi, Bradley Spencer-Dene, Philip Clarke, Enric Domingo, Eugene Tulchinsky, Robert G J Vries, David Kerr, Yihang Pan, Yulong He, David O Bates, Ian Tomlinson, Hans Clevers, Abdolrahman S Nateri

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

Colorectal cancer (CRC) patients develop recurrence after chemotherapy owing to the survival of stem cell-like cells referred to as cancer stem-like cells (CSCs). The origin of CSCs is linked to the epithelial-mesenchymal transition (EMT) process. Currently, it remains poorly understood how EMT programmes enable CSCs residing in the tumour microenvironment to escape the effects of chemotherapy. This study identifies a key molecular pathway that is responsible for the formation of drug-resistant CSC populations. Using a modified yeast-2-hybrid system and 2D gel-based proteomics methods, we show that the E3-ubiquitin ligase FBXW7 directly binds and degrades the EMT-inducing transcription factor ZEB2 in a phosphorylation-dependent manner. Loss of FBXW7 induces an EMT that can be effectively reversed by knockdown of ZEB2. The FBXW7-ZEB2 axis regulates such important cancer cell features, as stemness/dedifferentiation, chemoresistance and cell migration in vitro, ex vivo and in animal models of metastasis. High expression of ZEB2 in cancer tissues defines the reduced ZEB2 expression in the cancer-associated stroma in patients and in murine intestinal organoids, demonstrating a tumour-stromal crosstalk that modulates a niche and EMT activation. Our study thus uncovers a new molecular mechanism, by which the CRC cells display differences in resistance to chemotherapy and metastatic potential.

Original languageEnglish
Pages (from-to)13
JournalOncogenesis
Volume8
Issue number3
DOIs
Publication statusPublished - 19 Feb 2019

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    Li, N., Babaei-Jadidi, R., Lorenzi, F., Spencer-Dene, B., Clarke, P., Domingo, E., Tulchinsky, E., Vries, R. G. J., Kerr, D., Pan, Y., He, Y., Bates, D. O., Tomlinson, I., Clevers, H., & Nateri, A. S. (2019). An FBXW7-ZEB2 axis links EMT and tumour microenvironment to promote colorectal cancer stem cells and chemoresistance. Oncogenesis, 8(3), 13. https://doi.org/10.1038/s41389-019-0125-3