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Oncostatin M promotes cancer cell plasticity through cooperative STAT3-SMAD3 signaling

Increasing evidence supports the idea that cancer cell plasticity promotes metastasis and tumor recurrence, resulting in patient mortality. While it is clear that the tumor microenvironment (TME) contributes to cancer cell plasticity, the specific TME factors most actively controlling plasticity rem...

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Autores principales: Junk, D J, Bryson, B L, Smigiel, J M, Parameswaran, N, Bartel, C A, Jackson, M W
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509502/
https://www.ncbi.nlm.nih.gov/pubmed/28288136
http://dx.doi.org/10.1038/onc.2017.33
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author Junk, D J
Bryson, B L
Smigiel, J M
Parameswaran, N
Bartel, C A
Jackson, M W
author_facet Junk, D J
Bryson, B L
Smigiel, J M
Parameswaran, N
Bartel, C A
Jackson, M W
author_sort Junk, D J
collection PubMed
description Increasing evidence supports the idea that cancer cell plasticity promotes metastasis and tumor recurrence, resulting in patient mortality. While it is clear that the tumor microenvironment (TME) contributes to cancer cell plasticity, the specific TME factors most actively controlling plasticity remain largely unknown. Here, we performed a screen to identify TME cytokines and growth factors that promote epithelial–mesenchymal plasticity, and acquisition of cancer stem cell (CSC) properties. Of 28 TME cytokines and growth factors tested, we identified Oncostatin M (OSM) as the most potent inducer of mesenchymal/CSC properties. OSM-induced plasticity was Signal Transducer and Activator of Transcription 3 (STAT3)-dependent, and also required a novel intersection with transforming growth factor-β (TGF-β)/SMAD signaling. OSM/STAT3 activation promoted SMAD3 nuclear accumulation, DNA binding and induced SMAD3-dependent transcriptional activity. Suppression of TGF-β receptor activity or ablation of SMAD3 or SMAD4, but not SMAD2, strongly suppressed OSM/STAT3-mediated plasticity. Moreover, removal of OSM or inhibition of STAT3 or SMAD3 resulted in a marked reversion to a non-invasive, epithelial phenotype. We propose that targeted blockade of the STAT3/SMAD3 axis in tumor cells may represent a novel therapeutic approach to prevent the plasticity required for metastatic progression and tumor recurrence.
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spelling pubmed-55095022017-07-19 Oncostatin M promotes cancer cell plasticity through cooperative STAT3-SMAD3 signaling Junk, D J Bryson, B L Smigiel, J M Parameswaran, N Bartel, C A Jackson, M W Oncogene Original Article Increasing evidence supports the idea that cancer cell plasticity promotes metastasis and tumor recurrence, resulting in patient mortality. While it is clear that the tumor microenvironment (TME) contributes to cancer cell plasticity, the specific TME factors most actively controlling plasticity remain largely unknown. Here, we performed a screen to identify TME cytokines and growth factors that promote epithelial–mesenchymal plasticity, and acquisition of cancer stem cell (CSC) properties. Of 28 TME cytokines and growth factors tested, we identified Oncostatin M (OSM) as the most potent inducer of mesenchymal/CSC properties. OSM-induced plasticity was Signal Transducer and Activator of Transcription 3 (STAT3)-dependent, and also required a novel intersection with transforming growth factor-β (TGF-β)/SMAD signaling. OSM/STAT3 activation promoted SMAD3 nuclear accumulation, DNA binding and induced SMAD3-dependent transcriptional activity. Suppression of TGF-β receptor activity or ablation of SMAD3 or SMAD4, but not SMAD2, strongly suppressed OSM/STAT3-mediated plasticity. Moreover, removal of OSM or inhibition of STAT3 or SMAD3 resulted in a marked reversion to a non-invasive, epithelial phenotype. We propose that targeted blockade of the STAT3/SMAD3 axis in tumor cells may represent a novel therapeutic approach to prevent the plasticity required for metastatic progression and tumor recurrence. Nature Publishing Group 2017-07-13 2017-03-13 /pmc/articles/PMC5509502/ /pubmed/28288136 http://dx.doi.org/10.1038/onc.2017.33 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Original Article
Junk, D J
Bryson, B L
Smigiel, J M
Parameswaran, N
Bartel, C A
Jackson, M W
Oncostatin M promotes cancer cell plasticity through cooperative STAT3-SMAD3 signaling
title Oncostatin M promotes cancer cell plasticity through cooperative STAT3-SMAD3 signaling
title_full Oncostatin M promotes cancer cell plasticity through cooperative STAT3-SMAD3 signaling
title_fullStr Oncostatin M promotes cancer cell plasticity through cooperative STAT3-SMAD3 signaling
title_full_unstemmed Oncostatin M promotes cancer cell plasticity through cooperative STAT3-SMAD3 signaling
title_short Oncostatin M promotes cancer cell plasticity through cooperative STAT3-SMAD3 signaling
title_sort oncostatin m promotes cancer cell plasticity through cooperative stat3-smad3 signaling
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509502/
https://www.ncbi.nlm.nih.gov/pubmed/28288136
http://dx.doi.org/10.1038/onc.2017.33
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