Coupling the modules of EMT and stemness: A tunable ‘stemness window’ model

Abstract

Metastasis of carcinoma involves migration of tumor cells to distant organs and initiate secondary tumors. Migration requires a complete or partial Epithelial-to-Mesenchymal Transition (EMT), and tumor-initiation requires cells possessing stemness. Epithelial cells (E) undergoing a complete EMT to become mesenchymal (M) have been suggested to be more likely to possess stemness. However, recent studies suggest that stemness can also be associated with cells undergoing a partial EMT (hybrid E/M phenotype). Therefore, the correlation between EMT and stemness remains elusive. Here, using a theoretical framework that couples the core EMT and stemness modules (miR-200/ZEB and LIN28/let-7), we demonstrate that the positioning of ‘stemness window’ on the ‘EMT axis’ need not be universal; rather it can be fine-tuned. Particularly, we present OVOL as an example of a modulating factor that, due to its coupling with miR-200/ZEB/LIN28/let-7 circuit, fine-tunes the EMT-stemness interplay. Coupling OVOL can inhibit the stemness likelihood of M and elevate that of the hybrid E/M (partial EMT) phenotype, thereby pulling the ‘stemness window’ away from the M end of ‘EMT axis’. Our results unify various apparently contradictory experimental findings regarding the interconnection between EMT and stemness, corroborate the emerging notion that partial EMT associates with stemness, and offer new testable predictions.

MicroRNA-141 suppresses prostate cancer stem cells and metastasis by targeting a cohort of pro-metastasis genes

“…These latter observations suggest that miR-141 might be inducing a ‘partial' MET phenotype2728343536 in PCa cells in that it induces a strong epithelial phenotype (evidenced by increased CDH1) but only a partial loss of mesenchymal genes. Recent studies have suggested that CSCs may not always be associated with a complete mesenchymal phenotype—rather, cancer cells with a partial EMT phenotype that allows a great proliferative capability of epithelial cells and the morphological plasticity of mesenchymal cells will have the best chance to survive and establish a tumour or metastatic colony363738. Consistent with this notion, CD44 + PCa/HPCa cells, although possessing high clonogenic, tumour-regenerating and metastatic potentials1320212325, did not manifest a ‘pure' mesenchymal gene expression profile (Supplementary Fig.…”

EMT, CSCs, and drug resistance: the mechanistic link and clinical implications

“…Thus, while EMT-programme activation in the otherwise-epithelial carcinoma cells generally results in an enhanced potential for tumorigenesis, full activation of the entire EMT programme — that is, complete transition to a mesenchymal cell type — has been found to be detrimental to tumorigenic activity 88,148,187 . Moreover, under certain conditions, CSCs can undergo phenotypic drift, thus losing mesenchymal traits while maintaining their tumorigenic activity 146,147 .…”

“…1b). This finding explains why increasing attention is being placed on the ‘partial EMT’ state, which seems to be critical for the maximal tumorigenic activity of CSCs 148 . More specifically, in a model of claudin-low breast cancer, in which most carcinoma cells display a highly mesenchymal phenotype, a subpopulation of cells with relatively epithelial characteristics exhibited greater tumorigenic activity than the bulk population of the cells 149 .…”

Targeting TGF-β Signaling for Therapeutic Gain

“…The elusive tumor-initiating cell or CSC generates diverse progeny that lead to the characteristic heterogeneity of the tumor while also maintaining a self-propagating function that is essential for primary tumor growth and for seeding of tumors at distant metastases (Shipitsin et al 2007;Mani et al 2008). It is now widely accepted that EMT can generate a CSC-like state; indeed, this cell type is reported to occupy a partial EMT position with characteristics of both cell states (Kalluri and Weinberg 2009;Jolly et al 2015).…”