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dc.contributor.authorVasiliauskaite, Kotryna
dc.contributor.authorFleten, Karianne Giller
dc.contributor.authorBarkovskaya, Anna
dc.contributor.authorNygaard, Vigdis
dc.contributor.authorHaugen, Mads Haugland
dc.contributor.authorEngesæter, Birgit Øvstebø
dc.contributor.authorMælandsmo, Gunhild
dc.contributor.authorPrasmickaite, Lina
dc.date.accessioned2017-03-14T12:03:42Z
dc.date.available2017-03-14T12:03:42Z
dc.date.issued2016
dc.description.abstractThe 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.en_US
dc.description.sponsorshipThe project was supported by the Research Council of Norway (222262/F20), the Norwegian Cancer Society (730104), Einar Unsgaard and Kitty Unsgaard Legacy, as well as Astri and Birger Torsteds Legacy. The RPPA studies were supported by MDACC/CCSG grant P30 CA016672.en_US
dc.descriptionPublished version. Source at <a href=http://doi.org/10.18632/oncotarget.7671>http://doi.org/10.18632/oncotarget.7671</a>. License <a href=https://creativecommons.org/licenses/by/3.0/>CC BY 3.0</a>.en_US
dc.identifier.citationVasiliauskaite K, Fleten KG, Barkovskaya A, Nygaard V, Haugen MH, Engesæter BØ, Mælandsmo GM, Prasmickaite L. Fibroblast-induced switching to the mesenchymal-like phenotype and PI3K/mTOR signaling protects melanoma cells from BRAF inhibitors. OncoTarget. 2016;7(15):19997-20015en_US
dc.identifier.cristinIDFRIDAID 1367913
dc.identifier.doi10.18632/oncotarget.7671
dc.identifier.issn1949-2553
dc.identifier.urihttps://hdl.handle.net/10037/10647
dc.language.isoengen_US
dc.publisherImpact Journalsen_US
dc.relation.journalOncoTarget
dc.relation.projectIDinfo:eu-repo/grantAgreement/RCN//222262/Norway///en_US
dc.rights.accessRightsopenAccessen_US
dc.subjectVDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762en_US
dc.subjectmelanomaen_US
dc.subjectBRAF inhibitoren_US
dc.subjectresistanceen_US
dc.subjectphenotype switchen_US
dc.subjectfibroblastsen_US
dc.titleFibroblast-induced switching to the mesenchymal-like phenotype and PI3K/mTOR signaling protects melanoma cells from BRAF inhibitorsen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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