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Hybrid E/M phenotype(S) and stemness: A mechanistic connection embedded in network topology

Pasani, S and Sahoo, S and Jolly, MK (2021) Hybrid E/M phenotype(S) and stemness: A mechanistic connection embedded in network topology. In: Journal of Clinical Medicine, 10 (1). pp. 1-19.

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Official URL: https://doi.org/10.3390/jcm10010060


Metastasis remains an unsolved clinical challenge. Two crucial features of metastasizing cancer cells are (a) their ability to dynamically move along the epithelial–hybrid–mesenchymal spectrum and (b) their tumor initiation potential or stemness. With increasing functional characterization of hybrid epithelial/mesenchymal (E/M) phenotypes along the spectrum, recent in vitro and in vivo studies have suggested an increasing association of hybrid E/M phenotypes with stemness. However, the mechanistic underpinnings enabling this association remain unclear. Here, we develop a mechanism-based mathematical modeling framework that interrogates the emergent nonlinear dynamics of the coupled network modules regulating E/M plasticity (miR-200/ZEB) and stemness (LIN28/let-7). Simulating the dynamics of this coupled network across a large ensemble of parame-ter sets, we observe that hybrid E/M phenotype(s) are more likely to acquire stemness relative to “pure” epithelial or mesenchymal states. We also integrate multiple “phenotypic stability factors” (PSFs) that have been shown to stabilize hybrid E/M phenotypes both in silico and in vitro—such as OVOL1/2, GRHL2, and NRF2—with this network, and demonstrate that the enrichment of hybrid E/M phenotype(s) with stemness is largely conserved in the presence of these PSFs. Thus, our results offer mechanistic insights into recent experimental observations of hybrid E/M phenotype(s) that are essential for tumor initiation and highlight how this feature is embedded in the underlying topology of interconnected EMT (Epithelial-Mesenchymal Transition) and stemness networks.

Item Type: Journal Article
Publication: Journal of Clinical Medicine
Publisher: MDPI
Additional Information: The copyright for this article belongs to the Author.
Keywords: Epithelial–mesenchymal transition; Hybrid epithelial/mesenchymal; Phenotypic plasticity; Phenotypic stability factors; Stemness
Department/Centre: Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited: 31 Jul 2023 13:03
Last Modified: 31 Jul 2023 13:03
URI: https://eprints.iisc.ac.in/id/eprint/82699

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