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.

Silencing of TGM2 reverses epithelial to mesenchymal transition and modulates the chemosensitivity of breast cancer to docetaxel

“…The data presented in the present study suggest that the changes observed in TG2-expressing cells were associated with a mesenchymal phenotype. Downregulation of TG2 induces changes associated with EMT, for example, in morphology and EMT-relevant markers, which control chemoresistance (2).…”

“…EMT is a process by which epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties. The process also controls chemoresistance and immune escape (2).…”

Probing the Bi-directional Interaction Between Microglia and Gliomas in a Tumor Microenvironment on a Microdevice

“…This enhanced invasion capability in glioma is considered to be related to the EMT change of C6 cells, which is a crucial feature in tumor motility and invasiveness. EMT is a complicated biological cellular process that exhibits highly phenotypic plasticity, in which the cells lose their normal immobile and adhesion phenotype and acquire a mesenchymal phenotype to enhance their motility and invasiveness [36][37][38][39]. The EMT change of C6 cells also was investigated in this study.…”

Potential Anti-metastasis Natural Compounds for Lung Cancer

“…In NSCLC, the low vimentin level was found to be a predictor of better survival in primary NSCLC (51). EMT phenotypes in primary cells of lung cancer have been shown to link with anoikis and chemotherapeutic resistance (52,53). Focusing on cancer cells and their environment interplays, EMT can be induced by several Figure Table I.…”