Quantifying Cancer Epithelial-Mesenchymal Plasticity and its Association with Stemness and Immune Response

Abstract

Cancer cells can acquire a spectrum of stable hybrid epithelial/mesenchymal (E/M) states during epithelial–mesenchymal transition (EMT). Cells in these hybrid E/M phenotypes often combine epithelial and mesenchymal features and tend to migrate collectively commonly as small clusters. Such collectively migrating cancer cells play a pivotal role in seeding metastases and their presence in cancer patients indicates an adverse prognostic factor. Moreover, cancer cells in hybrid E/M phenotypes tend to be more associated with stemness which endows them with tumor-initiation ability and therapy resistance. Most recently, cells undergoing EMT have been shown to promote immune suppression for better survival. A systematic understanding of the emergence of hybrid E/M phenotypes and the connection of EMT with stemness and immune suppression would contribute to more effective therapeutic strategies. In this review, we first discuss recent efforts combining theoretical and experimental approaches to elucidate mechanisms underlying EMT multi-stability (i.e., the existence of multiple stable phenotypes during EMT) and the properties of hybrid E/M phenotypes. Following we discuss non-cell-autonomous regulation of EMT by cell cooperation and extracellular matrix. Afterwards, we discuss various metrics that can be used to quantify EMT spectrum. We further describe possible mechanisms underlying the formation of clusters of circulating tumor cells. Last but not least, we summarize recent systems biology analysis of the role of EMT in the acquisition of stemness and immune suppression.

NRF2 activates a partial Epithelial-Mesenchymal Transition and is maximally present in a hybrid Epithelial/Mesenchymal phenotype

“…However, EMT is not a binary process; instead, cells can also attain one or more hybrid epithelial/mesenchymal (E/M) phenotypes that may be more stem-like, metastatic and aggressive than those in completely epithelial or mesenchymal ones [1,2]. Cells in hybrid E/M phenotype(s) display a mix of epithelial and mesenchymal traits, thereby enabling collective cell migration leading to the formation of clusters of Circulating Tumour Cells (CTCs) that can form a large majority of metastases, and correlate with poor clinical outcome [3,4].…”

Anticipating critical transitions in epithelial-hybrid-mesenchymal cell-fate determination

“…Further, besides EMT, there are other axes of phenotypic plasticity in cancer, such as metabolic plasticity, switching back and forth between a cancer stem cell (CSCs) and a non-cancer stem cell. With recent developments in identifying the multistable dynamics of the networks regulating these transitions [59]. EWS analysis can be applied to these networks to identifying promising novel dynamic biomarkers.…”

New Insights Into the Role of Phenotypic Plasticity and EMT in Driving Cancer Progression

“…single cell or collective migration, and for co-culture studies (Sarioglu et al, 2015;Ma et al, 2018;Shang et al, 2019;Truong et al, 2019). Similarly, various mathematical approaches and modeling have been helpful in deciphering the significant genes and molecular networks associated with the spectrum of epithelial and mesenchymal states, as well as phenotypic plasticity (Jolly et al, 2017;Bocci et al, 2018;Jia et al, 2019;Yang et al, 2019). However, it is crucial to acknowledge that the modalities and analytical approaches utilized in the field of EMP present context-specific studies, such that inferences derived will not provide an overarching conclusion (Henkel et al, 2019).…”