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Fibroblast-induced switching to the mesenchymal-like phenotype and PI3K/mTOR signaling protects melanoma cells from BRAF inhibitors

The knowledge on how tumor-associated stroma influences efficacy of anti-cancer therapy just started to emerge. Here we show that lung fibroblasts reduce melanoma sensitivity to the BRAF inhibitor (BRAFi) vemurafenib only if the two cell types are in close proximity. In the presence of fibroblasts,...

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Autores principales: Seip, Kotryna, Fleten, Karianne G., Barkovskaya, Anna, Nygaard, Vigdis, Haugen, Mads H., Engesæter, Birgit Ø., Mælandsmo, Gunhild M., Prasmickaite, Lina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991434/
https://www.ncbi.nlm.nih.gov/pubmed/26918352
http://dx.doi.org/10.18632/oncotarget.7671
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author Seip, Kotryna
Fleten, Karianne G.
Barkovskaya, Anna
Nygaard, Vigdis
Haugen, Mads H.
Engesæter, Birgit Ø.
Mælandsmo, Gunhild M.
Prasmickaite, Lina
author_facet Seip, Kotryna
Fleten, Karianne G.
Barkovskaya, Anna
Nygaard, Vigdis
Haugen, Mads H.
Engesæter, Birgit Ø.
Mælandsmo, Gunhild M.
Prasmickaite, Lina
author_sort Seip, Kotryna
collection PubMed
description The knowledge on how tumor-associated stroma influences efficacy of anti-cancer therapy just started to emerge. Here we show that lung fibroblasts reduce melanoma sensitivity to the BRAF inhibitor (BRAFi) vemurafenib only if the two cell types are in close proximity. In the presence of fibroblasts, the adjacent melanoma cells acquire de-differentiated mesenchymal-like phenotype. Upon treatment with BRAFi, such melanoma cells maintain high levels of phospho ribosomal protein S6 (pS6), i.e. active mTOR signaling, which is suppressed in the BRAFi sensitive cells without stromal contacts. Inhibitors of PI3K/mTOR in combination with BRAFi eradicate pS6(high) cell subpopulations and potentiate anti-cancer effects in melanoma protected by the fibroblasts. mTOR and BRAF co-inhibition also delayed the development of early-stage lung metastases in vivo. In conclusion, we demonstrate that upon influence from fibroblasts, melanoma cells undergo a phenotype switch to the mesenchymal state, which can support PI3K/mTOR signaling. The lost sensitivity to BRAFi in such cells can be overcome by co-targeting PI3K/mTOR. This knowledge could be explored for designing BRAFi combination therapies aiming to eliminate both stroma-protected and non-protected counterparts of metastases.
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spelling pubmed-49914342016-09-01 Fibroblast-induced switching to the mesenchymal-like phenotype and PI3K/mTOR signaling protects melanoma cells from BRAF inhibitors Seip, Kotryna Fleten, Karianne G. Barkovskaya, Anna Nygaard, Vigdis Haugen, Mads H. Engesæter, Birgit Ø. Mælandsmo, Gunhild M. Prasmickaite, Lina Oncotarget Research Paper The knowledge on how tumor-associated stroma influences efficacy of anti-cancer therapy just started to emerge. Here we show that lung fibroblasts reduce melanoma sensitivity to the BRAF inhibitor (BRAFi) vemurafenib only if the two cell types are in close proximity. In the presence of fibroblasts, the adjacent melanoma cells acquire de-differentiated mesenchymal-like phenotype. Upon treatment with BRAFi, such melanoma cells maintain high levels of phospho ribosomal protein S6 (pS6), i.e. active mTOR signaling, which is suppressed in the BRAFi sensitive cells without stromal contacts. Inhibitors of PI3K/mTOR in combination with BRAFi eradicate pS6(high) cell subpopulations and potentiate anti-cancer effects in melanoma protected by the fibroblasts. mTOR and BRAF co-inhibition also delayed the development of early-stage lung metastases in vivo. In conclusion, we demonstrate that upon influence from fibroblasts, melanoma cells undergo a phenotype switch to the mesenchymal state, which can support PI3K/mTOR signaling. The lost sensitivity to BRAFi in such cells can be overcome by co-targeting PI3K/mTOR. This knowledge could be explored for designing BRAFi combination therapies aiming to eliminate both stroma-protected and non-protected counterparts of metastases. Impact Journals LLC 2016-02-24 /pmc/articles/PMC4991434/ /pubmed/26918352 http://dx.doi.org/10.18632/oncotarget.7671 Text en Copyright: © 2016 Seip et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Seip, Kotryna
Fleten, Karianne G.
Barkovskaya, Anna
Nygaard, Vigdis
Haugen, Mads H.
Engesæter, Birgit Ø.
Mælandsmo, Gunhild M.
Prasmickaite, Lina
Fibroblast-induced switching to the mesenchymal-like phenotype and PI3K/mTOR signaling protects melanoma cells from BRAF inhibitors
title Fibroblast-induced switching to the mesenchymal-like phenotype and PI3K/mTOR signaling protects melanoma cells from BRAF inhibitors
title_full Fibroblast-induced switching to the mesenchymal-like phenotype and PI3K/mTOR signaling protects melanoma cells from BRAF inhibitors
title_fullStr Fibroblast-induced switching to the mesenchymal-like phenotype and PI3K/mTOR signaling protects melanoma cells from BRAF inhibitors
title_full_unstemmed Fibroblast-induced switching to the mesenchymal-like phenotype and PI3K/mTOR signaling protects melanoma cells from BRAF inhibitors
title_short Fibroblast-induced switching to the mesenchymal-like phenotype and PI3K/mTOR signaling protects melanoma cells from BRAF inhibitors
title_sort fibroblast-induced switching to the mesenchymal-like phenotype and pi3k/mtor signaling protects melanoma cells from braf inhibitors
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991434/
https://www.ncbi.nlm.nih.gov/pubmed/26918352
http://dx.doi.org/10.18632/oncotarget.7671
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