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

doi:10.1038/s41389-019-0125-3

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

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

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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.

Originele taal-2	Engels
Pagina's (van-tot)	13
Tijdschrift	Oncogenesis
Volume	8
Nummer van het tijdschrift	3
DOI's	https://doi.org/10.1038/s41389-019-0125-3
Status	Gepubliceerd - 19 feb. 2019

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10.1038/s41389-019-0125-3

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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

@article{d8aa3a0431b6422f8042e82f68b4f607,

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

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.",

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

year = "2019",

month = feb,

day = "19",

doi = "10.1038/s41389-019-0125-3",

language = "English",

volume = "8",

pages = "13",

journal = "Oncogenesis",

issn = "2157-9024",

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

TY - JOUR

T1 - An FBXW7-ZEB2 axis links EMT and tumour microenvironment to promote colorectal cancer stem cells and chemoresistance

AU - Li, Ningning

AU - Babaei-Jadidi, Roya

AU - Lorenzi, Federica

AU - Spencer-Dene, Bradley

AU - Clarke, Philip

AU - Domingo, Enric

AU - Tulchinsky, Eugene

AU - Vries, Robert G J

AU - Kerr, David

AU - Pan, Yihang

AU - He, Yulong

AU - Bates, David O

AU - Tomlinson, Ian

AU - Clevers, Hans

AU - Nateri, Abdolrahman S

PY - 2019/2/19

Y1 - 2019/2/19

N2 - 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.

AB - 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.

U2 - 10.1038/s41389-019-0125-3

DO - 10.1038/s41389-019-0125-3

M3 - Article

C2 - 30783098

SN - 2157-9024

VL - 8

SP - 13

JO - Oncogenesis

JF - Oncogenesis

IS - 3

ER -

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

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