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

Kotryna Seip, Karianne G. Fleten, Anna Barkovskaya, Vigdis Nygaard, Mads H. Haugen, Birgit Engesæter, Gunhild M. Mælandsmo, Lina Prasmickaite

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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 pS6high 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.

Original languageEnglish (US)
Pages (from-to)19997-20015
Number of pages19
JournalOncotarget
Volume7
Issue number15
DOIs
StatePublished - Apr 12 2016

Fingerprint

Phosphatidylinositol 3-Kinases
Melanoma
Fibroblasts
Phenotype
Ribosomal Protein S6
Neoplasm Metastasis
Neoplasms
Lung
Stromal Cells
Therapeutics

Keywords

  • BRAF inhibitor
  • Fibroblasts
  • Melanoma
  • Phenotype switch
  • Resistance

ASJC Scopus subject areas

  • Oncology

Cite this

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; Mælandsmo, Gunhild M.; Prasmickaite, Lina.

In: Oncotarget, Vol. 7, No. 15, 12.04.2016, p. 19997-20015.

Research output: Contribution to journalArticle

@article{2ccf885056884272b6a9b52f203277cf,
title = "Fibroblast-induced switching to the mesenchymal-like phenotype and PI3K/mTOR signaling protects melanoma cells from BRAF inhibitors",
abstract = "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 pS6high 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.",
keywords = "BRAF inhibitor, Fibroblasts, Melanoma, Phenotype switch, Resistance",
author = "Kotryna Seip and Fleten, {Karianne G.} and Anna Barkovskaya and Vigdis Nygaard and Haugen, {Mads H.} and Birgit Enges{\ae}ter and M{\ae}landsmo, {Gunhild M.} and Lina Prasmickaite",
year = "2016",
month = "4",
day = "12",
doi = "10.18632/oncotarget.7671",
language = "English (US)",
volume = "7",
pages = "19997--20015",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "15",

}

TY - JOUR

T1 - Fibroblast-induced switching to the mesenchymal-like phenotype and PI3K/mTOR signaling protects melanoma cells from BRAF inhibitors

AU - Seip, Kotryna

AU - Fleten, Karianne G.

AU - Barkovskaya, Anna

AU - Nygaard, Vigdis

AU - Haugen, Mads H.

AU - Engesæter, Birgit

AU - Mælandsmo, Gunhild M.

AU - Prasmickaite, Lina

PY - 2016/4/12

Y1 - 2016/4/12

N2 - 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 pS6high 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.

AB - 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 pS6high 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.

KW - BRAF inhibitor

KW - Fibroblasts

KW - Melanoma

KW - Phenotype switch

KW - Resistance

UR - http://www.scopus.com/inward/record.url?scp=84964789940&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964789940&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.7671

DO - 10.18632/oncotarget.7671

M3 - Article

C2 - 26918352

AN - SCOPUS:84964789940

VL - 7

SP - 19997

EP - 20015

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 15

ER -