A systems view of epithelial–mesenchymal transition signaling states

Abstract

AbtractEpithelial–mesenchymal transition (EMT) is an important contributor to the invasion and metastasis of epithelial-derived cancers. While considerable effort has focused in the regulators involved in the transition process, we have focused on consequences of EMT to prosurvival signaling. Changes in distinct metastable and ‘epigentically-fixed’ EMT states were measured by correlation of protein, phosphoprotein, phosphopeptide and RNA transcript abundance. The assembly of 1167 modulated components into functional systems or machines simplified biological understanding and increased prediction confidence highlighting four functional groups: cell adhesion and migration, metabolism, transcription nodes and proliferation/survival networks. A coordinate metabolic reduction in a cluster of 17 free-radical stress pathway components was observed and correlated with reduced glycolytic and increased oxidative phosphorylation enzyme capacity, consistent with reduced cell cycling and reduced need for macromolecular biosynthesis in the mesenchymal state. An attenuation of EGFR autophosphorylation and a switch from autocrine to paracrine-competent EGFR signaling was implicated in the enablement of tumor cell chemotaxis. A similar attenuation of IGF1R, MET and RON signaling with EMT was observed. In contrast, EMT increased prosurvival autocrine IL11/IL6-JAK2-STAT signaling, autocrine fibronectin-integrin α5β1 activation, autocrine Axl/Tyro3/PDGFR/FGFR RTK signaling and autocrine TGFβR signaling. A relatively uniform loss of polarity and cell–cell junction linkages to actin cytoskeleton and intermediate filaments was measured at a systems level. A more heterogeneous gain of ECM remodeling and associated with invasion and migration was observed. Correlation to stem cell, EMT, invasion and metastasis datasets revealed the greatest similarity with normal and cancerous breast stem cell populations, CD49fhi/EpCAM-/lo and CD44hi/CD24lo, respectively.Electronic supplementary materialThe online version of this article (doi:10.1007/s10585-010-9367-3) contains supplementary material, which is available to authorized users.

Epithelial ovarian cancer stem cells: underlying complexity of a simple paradigm

“…Potentially, EOC cells with an enhanced capability to undergo EMT may have reduced anoikis (Huang 2013), enhanced motility and invasiveness, properties that might favour their survival, engraftment and tumourigenicity in the TIC xenograft model. While the literature does not support a consistent association of ovarian CSCs and the mesenchymal phenotype, models of a metastable phenotype which endows putative stem cells with the capability to readily transition between epithelial and mesenchymal phenotypes (Jordan et al 2011, Thomson et al 2011, Lu et al 2013) may apply to EOC.…”

The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

“…Bypasssignaling through activation of a distinct RTK is often seen during acquired EGFR-TKI resistance (61). Although EMT can be induced by RTKs, the process may later be independent of RTK signaling (62). Different stages of EMT exist, including a partial EMT stage with cell contacts, but upregulation of mesenchymal markers.…”

Epithelial-to-Mesenchymal Transition Rewires the Molecular Path to PI3K-Dependent Proliferation

“…Although a broader picture of EMT-associated changes in gene expression and signaling pathways is emerging (8)(9)(10)(11), the functional understanding of these changes remains incomplete. For example, a correlation between EMT status and EGF receptor (EGFR) dependency has been shown in cell lines and patients, where a more epithelial phenotype is associated with heightened sensitivity to EGFR inhibition (12)(13)(14).…”