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.
authors.affiliation: 1] Department of Obstetrics & Gynaecology, National University Hospital, Singapore 119228, Singapore [2] Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599.
authors.forename: R Y-J
authors.initials: RY
authors.lastname: Huang
authors.forename: M K
authors.initials: MK
authors.lastname: Wong
authors.forename: T Z
authors.initials: TZ
authors.lastname: Tan
authors.forename: K T
authors.initials: KT
authors.lastname: Kuay
authors.forename: A H C
authors.initials: AH
authors.lastname: Ng
authors.forename: V Y
authors.initials: VY
authors.lastname: Chung
authors.forename: Y-S
authors.initials: YS
authors.lastname: Chu
authors.forename: N
authors.initials: N
authors.lastname: Matsumura
authors.forename: H-C
authors.initials: HC
authors.lastname: Lai
authors.forename: Y F
authors.initials: YF
authors.lastname: Lee
authors.forename: W-J
authors.initials: WJ
authors.lastname: Sim
authors.forename: C
authors.initials: C
authors.lastname: Chai
authors.forename: E
authors.initials: E
authors.lastname: Pietschmann
authors.forename: S
authors.initials: S
authors.lastname: Mori
authors.forename: J J H
authors.initials: JJ
authors.lastname: Low
authors.forename: M
authors.initials: M
authors.lastname: Choolani
authors.forename: J P
authors.initials: JP
authors.lastname: Thiery
mesh_terms: D000818:Animals; D023102:Anoikis / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D052117:Benzodioxoles / Q000627:therapeutic use; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D011799:Quinazolines / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D052117:Benzodioxoles; D015820:Cadherins; D011799:Quinazolines; C515233:saracatinib