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Hybrid E/M Phenotype(s) and Stemness: A Mechanistic Connection Embedded in Network Topology
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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794989/ https://www.ncbi.nlm.nih.gov/pubmed/33375334 http://dx.doi.org/10.3390/jcm10010060 |
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author | Pasani, Satwik Sahoo, Sarthak Jolly, Mohit Kumar |
author_facet | Pasani, Satwik Sahoo, Sarthak Jolly, Mohit Kumar |
author_sort | Pasani, Satwik |
collection | PubMed |
description | 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 parameter 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. |
format | Online Article Text |
id | pubmed-7794989 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-77949892021-01-10 Hybrid E/M Phenotype(s) and Stemness: A Mechanistic Connection Embedded in Network Topology Pasani, Satwik Sahoo, Sarthak Jolly, Mohit Kumar J Clin Med Article 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 parameter 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. MDPI 2020-12-26 /pmc/articles/PMC7794989/ /pubmed/33375334 http://dx.doi.org/10.3390/jcm10010060 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Pasani, Satwik Sahoo, Sarthak Jolly, Mohit Kumar Hybrid E/M Phenotype(s) and Stemness: A Mechanistic Connection Embedded in Network Topology |
title | Hybrid E/M Phenotype(s) and Stemness: A Mechanistic Connection Embedded in Network Topology |
title_full | Hybrid E/M Phenotype(s) and Stemness: A Mechanistic Connection Embedded in Network Topology |
title_fullStr | Hybrid E/M Phenotype(s) and Stemness: A Mechanistic Connection Embedded in Network Topology |
title_full_unstemmed | Hybrid E/M Phenotype(s) and Stemness: A Mechanistic Connection Embedded in Network Topology |
title_short | Hybrid E/M Phenotype(s) and Stemness: A Mechanistic Connection Embedded in Network Topology |
title_sort | hybrid e/m phenotype(s) and stemness: a mechanistic connection embedded in network topology |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794989/ https://www.ncbi.nlm.nih.gov/pubmed/33375334 http://dx.doi.org/10.3390/jcm10010060 |
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