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Mapping phenotypic heterogeneity in melanoma onto the epithelial-hybrid-mesenchymal axis

Epithelial to mesenchymal transition (EMT) is a well-studied hallmark of epithelial-like cancers that is characterized by loss of epithelial markers and gain of mesenchymal markers. Melanoma, which is derived from melanocytes of the skin, also undergo phenotypic plasticity toward mesenchymal-like ph...

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Autores principales: Pillai, Maalavika, Rajaram, Gouri, Thakur, Pradipti, Agarwal, Nilay, Muralidharan, Srinath, Ray, Ankita, Barbhaya, Dev, Somarelli, Jason A., Jolly, Mohit Kumar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9395132/
https://www.ncbi.nlm.nih.gov/pubmed/36003764
http://dx.doi.org/10.3389/fonc.2022.913803
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author Pillai, Maalavika
Rajaram, Gouri
Thakur, Pradipti
Agarwal, Nilay
Muralidharan, Srinath
Ray, Ankita
Barbhaya, Dev
Somarelli, Jason A.
Jolly, Mohit Kumar
author_facet Pillai, Maalavika
Rajaram, Gouri
Thakur, Pradipti
Agarwal, Nilay
Muralidharan, Srinath
Ray, Ankita
Barbhaya, Dev
Somarelli, Jason A.
Jolly, Mohit Kumar
author_sort Pillai, Maalavika
collection PubMed
description Epithelial to mesenchymal transition (EMT) is a well-studied hallmark of epithelial-like cancers that is characterized by loss of epithelial markers and gain of mesenchymal markers. Melanoma, which is derived from melanocytes of the skin, also undergo phenotypic plasticity toward mesenchymal-like phenotypes under the influence of various micro-environmental cues. Our study connects EMT to the phenomenon of de-differentiation (i.e., transition from proliferative to more invasive phenotypes) observed in melanoma cells during drug treatment. By analyzing 78 publicly available transcriptomic melanoma datasets, we found that de-differentiation in melanoma is accompanied by upregulation of mesenchymal genes, but not necessarily a concomitant loss of an epithelial program, suggesting a more “one-dimensional” EMT that leads to a hybrid epithelial/mesenchymal phenotype. Samples lying in the hybrid epithelial/mesenchymal phenotype also correspond to the intermediate phenotypes in melanoma along the proliferative-invasive axis - neural crest and transitory ones. As melanoma cells progress along the invasive axis, the mesenchymal signature does not increase monotonically. Instead, we observe a peak in mesenchymal scores followed by a decline, as cells further de-differentiate. This biphasic response recapitulates the dynamics of melanocyte development, suggesting close interactions among genes controlling differentiation and mesenchymal programs in melanocytes. Similar trends were noted for metabolic changes often associated with EMT in carcinomas in which progression along mesenchymal axis correlates with the downregulation of oxidative phosphorylation, while largely maintaining glycolytic capacity. Overall, these results provide an explanation for how EMT and de-differentiation axes overlap with respect to their transcriptional and metabolic programs in melanoma.
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spelling pubmed-93951322022-08-23 Mapping phenotypic heterogeneity in melanoma onto the epithelial-hybrid-mesenchymal axis Pillai, Maalavika Rajaram, Gouri Thakur, Pradipti Agarwal, Nilay Muralidharan, Srinath Ray, Ankita Barbhaya, Dev Somarelli, Jason A. Jolly, Mohit Kumar Front Oncol Oncology Epithelial to mesenchymal transition (EMT) is a well-studied hallmark of epithelial-like cancers that is characterized by loss of epithelial markers and gain of mesenchymal markers. Melanoma, which is derived from melanocytes of the skin, also undergo phenotypic plasticity toward mesenchymal-like phenotypes under the influence of various micro-environmental cues. Our study connects EMT to the phenomenon of de-differentiation (i.e., transition from proliferative to more invasive phenotypes) observed in melanoma cells during drug treatment. By analyzing 78 publicly available transcriptomic melanoma datasets, we found that de-differentiation in melanoma is accompanied by upregulation of mesenchymal genes, but not necessarily a concomitant loss of an epithelial program, suggesting a more “one-dimensional” EMT that leads to a hybrid epithelial/mesenchymal phenotype. Samples lying in the hybrid epithelial/mesenchymal phenotype also correspond to the intermediate phenotypes in melanoma along the proliferative-invasive axis - neural crest and transitory ones. As melanoma cells progress along the invasive axis, the mesenchymal signature does not increase monotonically. Instead, we observe a peak in mesenchymal scores followed by a decline, as cells further de-differentiate. This biphasic response recapitulates the dynamics of melanocyte development, suggesting close interactions among genes controlling differentiation and mesenchymal programs in melanocytes. Similar trends were noted for metabolic changes often associated with EMT in carcinomas in which progression along mesenchymal axis correlates with the downregulation of oxidative phosphorylation, while largely maintaining glycolytic capacity. Overall, these results provide an explanation for how EMT and de-differentiation axes overlap with respect to their transcriptional and metabolic programs in melanoma. Frontiers Media S.A. 2022-08-08 /pmc/articles/PMC9395132/ /pubmed/36003764 http://dx.doi.org/10.3389/fonc.2022.913803 Text en Copyright © 2022 Pillai, Rajaram, Thakur, Agarwal, Muralidharan, Ray, Barbhaya, Somarelli and Jolly https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Pillai, Maalavika
Rajaram, Gouri
Thakur, Pradipti
Agarwal, Nilay
Muralidharan, Srinath
Ray, Ankita
Barbhaya, Dev
Somarelli, Jason A.
Jolly, Mohit Kumar
Mapping phenotypic heterogeneity in melanoma onto the epithelial-hybrid-mesenchymal axis
title Mapping phenotypic heterogeneity in melanoma onto the epithelial-hybrid-mesenchymal axis
title_full Mapping phenotypic heterogeneity in melanoma onto the epithelial-hybrid-mesenchymal axis
title_fullStr Mapping phenotypic heterogeneity in melanoma onto the epithelial-hybrid-mesenchymal axis
title_full_unstemmed Mapping phenotypic heterogeneity in melanoma onto the epithelial-hybrid-mesenchymal axis
title_short Mapping phenotypic heterogeneity in melanoma onto the epithelial-hybrid-mesenchymal axis
title_sort mapping phenotypic heterogeneity in melanoma onto the epithelial-hybrid-mesenchymal axis
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9395132/
https://www.ncbi.nlm.nih.gov/pubmed/36003764
http://dx.doi.org/10.3389/fonc.2022.913803
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