A computational systems biology approach identifies SLUG as a mediator of partial Epithelial-Mesenchymal Transition (EMT)

Abstract

Epithelial-mesenchymal plasticity comprises of reversible transitions among epithelial, hybrid epithelial/mesenchymal (E/M) and mesenchymal phenotypes, and underlies various aspects of aggressive tumor progression such as metastasis, therapy resistance and immune evasion. The process of cells attaining one or more hybrid E/M phenotypes is termed as partial EMT. Cells in hybrid E/M phenotype(s) can be more aggressive than those in either fully epithelial or mesenchymal state. Thus, identifying regulators of hybrid E/M phenotypes is essential to decipher the rheostats of phenotypic plasticity and consequent accelerators of metastasis. Here, using a computational systems biology approach, we demonstrate that SLUG (SNAIL2) – an EMT-inducing transcription factor – can inhibit cells from undergoing a complete EMT and thus stabilizing them in hybrid E/M phenotype(s). It expands the parametric range enabling the existence of a hybrid E/M phenotype, thereby behaving as a phenotypic stability factor (PSF). Our simulations suggest that this specific property of SLUG emerges from the topology of the regulatory network it forms with other key regulators of epithelial-mesenchymal plasticity. Clinical data suggests that SLUG associates with worse patient prognosis across multiple carcinomas. Together, our results indicate that SLUG can stabilize hybrid E/M phenotype(s).

A mechanistic model captures the emergence and implications of non-genetic heterogeneity and reversible drug resistance in ER+ breast cancer cells

“…The resultant distribution was visibly trimodal in nature ( Fig 1C ) with two dominant peaks corresponding to epithelial and mesenchymal phenotypes. The middle peak was smaller, suggesting the smaller abundance of hybrid E/M phenotypes expressing intermediate values of ZEB1 and miR-200, as earlier postulated (35) ( Fig S1C ). Similarly, the normalized frequency histogram of resistance score was bimodal, corroborated by existence of two distinct clusters along the ERα66-ERα36 axes ( Fig S1C ).…”

“…SLUG and ZEB1 are key EMT-inducing transcription factors that can regulate the expression of ERα66 and ERα36, thereby controlling tamoxifen resistance. SLUG and ZEB1 can repress ERα66 (28, 33), while ERα36 can enhances the expression of ZEB1 through SNAIL and/or by suppression of CDH1 (18, 34, 35). ZEB1 and miR-200 form a mutually inhibitory self-activatory feedback loop, and in conjunction with their interaction with SLUG, they determine the EMT phenotype of a cell (35).…”

Hybrid E/M Phenotype(s) and Stemness: A Mechanistic Connection Embedded in Network Topology

“…Thus, our results propose that. similar to variations in the ability of EMT-TFs to drive an EMT [ 80 , 81 ], MET-TFs may induce MET to varying degrees. Moreover, the epigenetic background of cells may alter the dynamics of EMT/MET and/or CSCs/non-CSCs and the interconnection between these two axes.…”

Emerging Concepts of Hybrid Epithelial-to-Mesenchymal Transition in Cancer Progression

“…The early hybrid E/M subpopulation shows inclination towards a hybrid E/M phenotype, the M subpopulation towards an M phenotype without spontaneous reversal towards an E phenotype and the hybrid E/M cells exhibit maximum plasticity as they are potent enough to give rise to both E and M phenotypes [ 13 ]. EMT or MET are not “all-or-none” processes; rather, cells can achieve one or more partial E/M states that may be more plastic in comparison with fully E or M cells [ 14 ]. In other words, the process of partial EMT is a dynamic transition of cells from the E to M phase.…”