An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530)

R. Y J Huang, M. K. Wong, T. Z. Tan, K. T. Kuay, A. H. C Ng, V. Y. Chung, Y. S. Chu, N. Matsumura, H. C. Lai, Y. F. Lee, W. J. Sim, C. Chai, E. Pietschmann, S. Mori, J. J H Low, M. Choolani, J. P. Thiery

Research output: Contribution to journalArticle

152 Citations (Scopus)

Abstract

The phenotypic transformation of well-differentiated epithelial carcinoma into a mesenchymal-like state provides cancer cells with the ability to disseminate locally and to metastasise. Different degrees of epithelial-mesenchymal transition (EMT) have been found to occur in carcinomas from breast, colon and ovarian carcinoma (OC), among others. Numerous studies have focused on bona fide epithelial and mesenchymal states but rarely on intermediate states. In this study, we describe a model system for appraising the spectrum of EMT using 43 well-characterised OC cell lines. Phenotypic EMT characterisation reveals four subgroups: Epithelial, Intermediate E, Intermediate M and Mesenchymal, which represent different epithelial-mesenchymal compositions along the EMT spectrum. In cell-based EMT-related functional studies, OC cells harbouring an Intermediate M phenotype are characterised by high N-cadherin and ZEB1 expression and low E-cadherin and ERBB3/HER3 expression and are more anoikis-resistant and spheroidogenic. A specific Src-kinase inhibitor, Saracatinib (AZD0530), restores E-cadherin expression in Intermediate M cells in in vitro and in vivo models and abrogates spheroidogenesis. We show how a 33-gene EMT Signature can sub-classify an OC cohort into four EMT States correlating with progression-free survival (PFS). We conclude that the characterisation of intermediate EMT states provides a new approach to better define EMT. The concept of the EMT Spectrum allows the utilisation of EMT genes as predictive markers and the design and application of therapeutic targets for reversing EMT in a selective subgroup of patients.

Original languageEnglish
Article numbere915
JournalCell Death and Disease
Volume4
Issue number11
DOIs
Publication statusPublished - Nov 2013
Externally publishedYes

Fingerprint

Anoikis
Epithelial-Mesenchymal Transition
src-Family Kinases
Cadherins
Carcinoma
saracatinib
Genes
Disease-Free Survival

Keywords

  • Epithelial-mesenchymal transition
  • Intermediate states
  • Ovarian cancer

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530). / Huang, R. Y J; Wong, M. K.; Tan, T. Z.; Kuay, K. T.; C Ng, A. H.; Chung, V. Y.; Chu, Y. S.; Matsumura, N.; Lai, H. C.; Lee, Y. F.; Sim, W. J.; Chai, C.; Pietschmann, E.; Mori, S.; Low, J. J H; Choolani, M.; Thiery, J. P.

In: Cell Death and Disease, Vol. 4, No. 11, e915, 11.2013.

Research output: Contribution to journalArticle

Huang, RYJ, Wong, MK, Tan, TZ, Kuay, KT, C Ng, AH, Chung, VY, Chu, YS, Matsumura, N, Lai, HC, Lee, YF, Sim, WJ, Chai, C, Pietschmann, E, Mori, S, Low, JJH, Choolani, M & Thiery, JP 2013, 'An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530)', Cell Death and Disease, vol. 4, no. 11, e915. https://doi.org/10.1038/cddis.2013.442
Huang, R. Y J ; Wong, M. K. ; Tan, T. Z. ; Kuay, K. T. ; C Ng, A. H. ; Chung, V. Y. ; Chu, Y. S. ; Matsumura, N. ; Lai, H. C. ; Lee, Y. F. ; Sim, W. J. ; Chai, C. ; Pietschmann, E. ; Mori, S. ; Low, J. J H ; Choolani, M. ; Thiery, J. P. / An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530). In: Cell Death and Disease. 2013 ; Vol. 4, No. 11.
@article{fcaf3ad0f5014e46a5d226aeaf5bdb8b,
title = "An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530)",
abstract = "The phenotypic transformation of well-differentiated epithelial carcinoma into a mesenchymal-like state provides cancer cells with the ability to disseminate locally and to metastasise. Different degrees of epithelial-mesenchymal transition (EMT) have been found to occur in carcinomas from breast, colon and ovarian carcinoma (OC), among others. Numerous studies have focused on bona fide epithelial and mesenchymal states but rarely on intermediate states. In this study, we describe a model system for appraising the spectrum of EMT using 43 well-characterised OC cell lines. Phenotypic EMT characterisation reveals four subgroups: Epithelial, Intermediate E, Intermediate M and Mesenchymal, which represent different epithelial-mesenchymal compositions along the EMT spectrum. In cell-based EMT-related functional studies, OC cells harbouring an Intermediate M phenotype are characterised by high N-cadherin and ZEB1 expression and low E-cadherin and ERBB3/HER3 expression and are more anoikis-resistant and spheroidogenic. A specific Src-kinase inhibitor, Saracatinib (AZD0530), restores E-cadherin expression in Intermediate M cells in in vitro and in vivo models and abrogates spheroidogenesis. We show how a 33-gene EMT Signature can sub-classify an OC cohort into four EMT States correlating with progression-free survival (PFS). We conclude that the characterisation of intermediate EMT states provides a new approach to better define EMT. The concept of the EMT Spectrum allows the utilisation of EMT genes as predictive markers and the design and application of therapeutic targets for reversing EMT in a selective subgroup of patients.",
keywords = "Epithelial-mesenchymal transition, Intermediate states, Ovarian cancer",
author = "Huang, {R. Y J} and Wong, {M. K.} and Tan, {T. Z.} and Kuay, {K. T.} and {C Ng}, {A. H.} and Chung, {V. Y.} and Chu, {Y. S.} and N. Matsumura and Lai, {H. C.} and Lee, {Y. F.} and Sim, {W. J.} and C. Chai and E. Pietschmann and S. Mori and Low, {J. J H} and M. Choolani and Thiery, {J. P.}",
year = "2013",
month = "11",
doi = "10.1038/cddis.2013.442",
language = "English",
volume = "4",
journal = "Cell Death and Disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",
number = "11",

}

TY - JOUR

T1 - An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530)

AU - Huang, R. Y J

AU - Wong, M. K.

AU - Tan, T. Z.

AU - Kuay, K. T.

AU - C Ng, A. H.

AU - Chung, V. Y.

AU - Chu, Y. S.

AU - Matsumura, N.

AU - Lai, H. C.

AU - Lee, Y. F.

AU - Sim, W. J.

AU - Chai, C.

AU - Pietschmann, E.

AU - Mori, S.

AU - Low, J. J H

AU - Choolani, M.

AU - Thiery, J. P.

PY - 2013/11

Y1 - 2013/11

N2 - The phenotypic transformation of well-differentiated epithelial carcinoma into a mesenchymal-like state provides cancer cells with the ability to disseminate locally and to metastasise. Different degrees of epithelial-mesenchymal transition (EMT) have been found to occur in carcinomas from breast, colon and ovarian carcinoma (OC), among others. Numerous studies have focused on bona fide epithelial and mesenchymal states but rarely on intermediate states. In this study, we describe a model system for appraising the spectrum of EMT using 43 well-characterised OC cell lines. Phenotypic EMT characterisation reveals four subgroups: Epithelial, Intermediate E, Intermediate M and Mesenchymal, which represent different epithelial-mesenchymal compositions along the EMT spectrum. In cell-based EMT-related functional studies, OC cells harbouring an Intermediate M phenotype are characterised by high N-cadherin and ZEB1 expression and low E-cadherin and ERBB3/HER3 expression and are more anoikis-resistant and spheroidogenic. A specific Src-kinase inhibitor, Saracatinib (AZD0530), restores E-cadherin expression in Intermediate M cells in in vitro and in vivo models and abrogates spheroidogenesis. We show how a 33-gene EMT Signature can sub-classify an OC cohort into four EMT States correlating with progression-free survival (PFS). We conclude that the characterisation of intermediate EMT states provides a new approach to better define EMT. The concept of the EMT Spectrum allows the utilisation of EMT genes as predictive markers and the design and application of therapeutic targets for reversing EMT in a selective subgroup of patients.

AB - The phenotypic transformation of well-differentiated epithelial carcinoma into a mesenchymal-like state provides cancer cells with the ability to disseminate locally and to metastasise. Different degrees of epithelial-mesenchymal transition (EMT) have been found to occur in carcinomas from breast, colon and ovarian carcinoma (OC), among others. Numerous studies have focused on bona fide epithelial and mesenchymal states but rarely on intermediate states. In this study, we describe a model system for appraising the spectrum of EMT using 43 well-characterised OC cell lines. Phenotypic EMT characterisation reveals four subgroups: Epithelial, Intermediate E, Intermediate M and Mesenchymal, which represent different epithelial-mesenchymal compositions along the EMT spectrum. In cell-based EMT-related functional studies, OC cells harbouring an Intermediate M phenotype are characterised by high N-cadherin and ZEB1 expression and low E-cadherin and ERBB3/HER3 expression and are more anoikis-resistant and spheroidogenic. A specific Src-kinase inhibitor, Saracatinib (AZD0530), restores E-cadherin expression in Intermediate M cells in in vitro and in vivo models and abrogates spheroidogenesis. We show how a 33-gene EMT Signature can sub-classify an OC cohort into four EMT States correlating with progression-free survival (PFS). We conclude that the characterisation of intermediate EMT states provides a new approach to better define EMT. The concept of the EMT Spectrum allows the utilisation of EMT genes as predictive markers and the design and application of therapeutic targets for reversing EMT in a selective subgroup of patients.

KW - Epithelial-mesenchymal transition

KW - Intermediate states

KW - Ovarian cancer

UR - http://www.scopus.com/inward/record.url?scp=84889570568&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84889570568&partnerID=8YFLogxK

U2 - 10.1038/cddis.2013.442

DO - 10.1038/cddis.2013.442

M3 - Article

C2 - 24201814

AN - SCOPUS:84889570568

VL - 4

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

IS - 11

M1 - e915

ER -