Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Pasani, Satwik, Sahoo, Sarthak, Jolly, Mohit Kumar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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
_version_ 1783634338394406912
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
work_keys_str_mv AT pasanisatwik hybridemphenotypesandstemnessamechanisticconnectionembeddedinnetworktopology
AT sahoosarthak hybridemphenotypesandstemnessamechanisticconnectionembeddedinnetworktopology
AT jollymohitkumar hybridemphenotypesandstemnessamechanisticconnectionembeddedinnetworktopology