Stability of the hybrid epithelial/mesenchymal phenotype

Abstract

Epithelial-to-Mesenchymal Transition (EMT) and its reverse – Mesenchymal to Epithelial Transition (MET) – are hallmarks of cellular plasticity during embryonic development and cancer metastasis. During EMT, epithelial cells lose cell-cell adhesion and gain migratory and invasive traits either partially or completely, leading to a hybrid epithelial/mesenchymal (hybrid E/M) or a mesenchymal phenotype respectively. Mesenchymal cells move individually, but hybrid E/M cells migrate collectively as observed during gastrulation, wound healing, and the formation of tumor clusters detected as Circulating Tumor Cells (CTCs). Typically, the hybrid E/M phenotype has largely been tacitly assumed to be transient and ‘metastable’. Here, we identify certain ‘phenotypic stability factors’ (PSFs) such as GRHL2 that couple to the core EMT decision-making circuit (miR-200/ZEB) and stabilize hybrid E/M phenotype. Further, we show that H1975 lung cancer cells can display a stable hybrid E/M phenotype and migrate collectively, a behavior that is impaired by knockdown of GRHL2 and another previously identified PSF - OVOL. In addition, our computational model predicts that GRHL2 can also associate hybrid E/M phenotype with high tumor-initiating potential, a prediction strengthened by the observation that the higher levels of these PSFs may be predictive of poor patient outcome. Finally, based on these specific examples, we deduce certain network motifs that can stabilize the hybrid E/M phenotype. Our results suggest that partial EMT, i.e. a hybrid E/M phenotype, need not be ‘metastable’, and strengthen the emerging notion that partial EMT, but not necessarily a complete EMT, is associated with aggressive tumor progression.

Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells

“…These observations hold implications for the nature of CSCs. Thus, activation of an EMT program appears to be productive for generating CSCs if it permits carcinoma cells to acquire certain mesenchymal traits, while retaining certain epithelial characteristics (1,11,24,34,39). This finding would explain why forced entrance of epithelial cells into a fully mesenchymal state is actually counterproductive for the formation of CSCs; we suspect that similar rules apply to normal nonneoplastic epithelial cells and their corresponding subpopulations of SCs.…”

“…In the case of carcinomas, one major source of heterogeneity, which has been the focus of a large body of research over the past decade, derives from differences between carcinoma cells that reside in epithelial versus mesenchymal cell states (1,11,24,33,34). Indeed, conversions between these states have been shown to occur as a result of activating cell-biological programs that result in epithelial-tomesenchymal and mesenchymal-to-epithelial transitions.…”

Survival Outcomes in Cancer Patients Predicted by a Partial EMT Gene Expression Scoring Metric

“…Moreover, the hybrid E/M phenotype has been tacitly assumed to be metastable or transient [11]. Recent studies, however, have challenged this assumption by demonstrating that a hybrid E/M phenotype can be stably maintained in vitro at a single-cell level, especially under the influence of factors such as GRHL2 and OVOL2 that contribute to the stability of a hybrid E/M phenotype [12–14]. These factors are referred to as ‘phenotypic stability factors’ (PSFs), and their elevated expression, indicative of a stable hybrid E/M levels, are associated with worse patient survival [12].…”

Grainyhead-like 2 in development and cancer

“…In addition to the direct regulation on EMT, GRHL2 can stabilize hybrid epithelial/mesenchymal phenotype of lung cancer cells which is associated with aggressive tumor progression. 48 Transforming growth factor-β (TGF-β) is a cytokine that can act as both oncogene and tumor suppressor. It inhibits tumor growth by inducing cell cycle arrest and it induces EMT to promote tumor metastasis.…”