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

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


Ningning Li

Frederica Lorenzi

Bradley Spencer-Dene

Philip Clarke

Enric Domingo

Eugene Tulchinsky

Robert G.J. Vries

David Kerr

Yihang Pan

Yulong He

Professor of Oncology

Ian Tomlinson

Hans Clevers


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.


Li, N., Babaei-Jadidi, R., Lorenzi, F., Spencer-Dene, B., Clarke, P., Domingo, E., …Nateri, A. S. (2019). An FBXW7-ZEB2 axis links EMT and tumour microenvironment to promote colorectal cancer stem cells and chemoresistance. Oncogenesis, 8, Article 13.

Journal Article Type Article
Acceptance Date Feb 4, 2019
Online Publication Date Feb 19, 2019
Publication Date Feb 19, 2019
Deposit Date Feb 18, 2019
Publicly Available Date Feb 20, 2019
Journal Oncogenesis
Electronic ISSN 2157-9024
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 8
Article Number 13
Keywords Chemoresistance; Colorectal CSCs; Epithelial-mesenchymal transition; Tumour microenvironment; FBXW7/ZEB2
Public URL
Publisher URL
Additional Information Received: 18 January 2019; Accepted: 3 February 2019; First Online: 19 February 2019; : The authors declare that they have no conflict of interest.


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