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dc.contributor.authorSeip, Kotryna
dc.contributor.authorJørgensen, Kjetil Nordbø
dc.contributor.authorHaselager, Marco Vincent
dc.contributor.authorAlbrecht, Marco
dc.contributor.authorHaugen, Mads Haugland
dc.contributor.authorEgeland, Eivind Valen
dc.contributor.authorLucarelli, Philippe
dc.contributor.authorEngebråten, Olav
dc.contributor.authorSauter, Thomas
dc.contributor.authorMælandsmo, Gunhild Mari
dc.contributor.authorPrasmickaite, Lina
dc.date.accessioned2020-06-30T09:49:46Z
dc.date.available2020-06-30T09:49:46Z
dc.date.issued2018-09-18
dc.description.abstractCancer cells' phenotypic plasticity, promoted by stromal cells, contributes to intra-tumoral heterogeneity and affects response to therapy. We have disclosed an association between fibroblast-stimulated phenotype switching and resistance to the clinically used BRAF inhibitor (BRAFi) vemurafenib in malignant melanoma, revealing a challenge in targeting the fibroblast-induced phenotype. Here we compared molecular features and drug sensitivity in melanoma cells grown as co-cultures with fibroblasts versus mono-cultures. In the presence of fibroblasts, melanoma cells switched to the dedifferentiated, mesenchymal-like, inflammatory phenotype that showed reduced sensitivity to the most of 275 tested cancer drugs. Fibroblasts, however, sensitized melanoma cells to PI3K inhibitors (PI3Ki) and particularly the inhibitor of GSK3, AR-A014418 (GSK3i), that showed superior efficacy in co-cultures. The proteome changes induced by the BRAFi + GSK3i combination mimicked changes induced by BRAFi in mono-cultures, and GSK3i in co-cultures. This suggests that the single drug drives the response to the combination treatment, depending on fibroblast presence or absence, consequently, phenotype. We propose that the BRAFi and GSK3i (or PI3Ki) combination exemplifies phenotype-specific combinatorial treatment that should be beneficial in phenotypically heterogeneous tumors rich in stromal interactions.en_US
dc.identifier.citationSeip, K., Jørgensen K., Haselager, M.V., Albrecht, M., Haugen, M.H., Egeland, E.V., ... Prasmickaite, L. (2018). Stroma-induced phenotypic plasticity offers phenotype-specific targeting to improve melanoma treatment. <i>Cancer Letters, 439</i>, 1-13. https://doi.org/10.1016/j.canlet.2018.09.023en_US
dc.identifier.cristinIDFRIDAID 1622379
dc.identifier.doi10.1016/j.canlet.2018.09.023
dc.identifier.issn0304-3835
dc.identifier.issn1872-7980
dc.identifier.urihttps://hdl.handle.net/10037/18712
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.relation.journalCancer Letters
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2018 Elsevier B.V.en_US
dc.subjectVDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762en_US
dc.subjectVDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762en_US
dc.subjectPhenotype switchingen_US
dc.subjectMelanomaen_US
dc.subjectCancer-associated fibroblastsen_US
dc.subjectDrug resistanceen_US
dc.subjectTumor-stroma interactionsen_US
dc.titleStroma-induced phenotypic plasticity offers phenotype-specific targeting to improve melanoma treatmenten_US
dc.type.versionacceptedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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