Extracellular Vesicle-Packaged miR-195-5p Sensitizes Melanoma to Targeted Therapy with Kinase Inhibitors

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dc.contributor.authorSantos, Nathalia L.
dc.contributor.authorBustos, Silvina O.
dc.contributor.authorReis, Patricia P. [UNESP]
dc.contributor.authorChammas, Roger
dc.contributor.authorAndrade, Luciana N. S.
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionUniversidade Estadual Paulista (UNESP)
dc.date.accessioned2023-07-29T13:54:55Z
dc.date.available2023-07-29T13:54:55Z
dc.date.issued2023-05-01
dc.description.abstractManagement of advanced melanoma remains challenging, with most BRAF (B-Raf proto-oncogene, serine/threonine kinase)-mutated metastatic patients relapsing within a few months upon MAPK inhibitors treatment. Modulation of tumor-derived extracellular vesicle (EVs) cargo with enrichment of antitumoral molecules is a promising strategy to impair tumor progression and increase treatment response. Herein, we report that restored expression of miR-195-5p, down-regulated in melanoma favoring drug resistance, increases the release of EVs enriched in the tumor suppressor miRNAs, miR-195-5p, miR-152-3p, and miR-202-3p. Incorporating these EVs by bystander tumor cells resulted in decreased proliferation and viability, accompanied by a reduction in CCND1 and YAP1 mRNA levels. Upon treatment with MAPK inhibitors, miR-195 EVs significantly decreased BCL2-L1 protein levels and increased cell death ratio and treatment efficacy. Additionally, EVs exogenously loaded with miR-195-5p by electroporation reduced tumor volume in vivo and impaired engraftment and growth of xenografts implanted with melanoma cells exposed to MAPK inhibitors. Our study shows that miR-195-5p antitumoral activity can be spread to bystander cells through EVs, improving melanoma response to targeted therapy and revealing a promising EV-based strategy to increase clinical response in patients harboring BRAF mutations.en
dc.description.affiliationCenter for Translational Research in Oncology (LIM24) Instituto do Câncer do Estado de São Paulo Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo Comprehensive Center for Precision Oncology Universidade de São Paulo
dc.description.affiliationDepartment of Surgery and Orthopedics and Experimental Research Unity (UNIPEX) Faculdade de Medicina Universidade Estadual Paulista (UNESP)
dc.description.affiliationUnespDepartment of Surgery and Orthopedics and Experimental Research Unity (UNIPEX) Faculdade de Medicina Universidade Estadual Paulista (UNESP)
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipIdFAPESP: 2019/07278-0
dc.description.sponsorshipIdCNPq: 305700/2017-0
dc.identifierhttp://dx.doi.org/10.3390/cells12091317
dc.identifier.citationCells, v. 12, n. 9, 2023.
dc.identifier.doi10.3390/cells12091317
dc.identifier.issn2073-4409
dc.identifier.scopus2-s2.0-85159201763
dc.identifier.urihttp://hdl.handle.net/11449/248830
dc.language.isoeng
dc.relation.ispartofCells
dc.sourceScopus
dc.subjectextracellular vesicles
dc.subjectMAPK inhibitors
dc.subjectmelanoma
dc.subjectmiR-195-5p
dc.titleExtracellular Vesicle-Packaged miR-195-5p Sensitizes Melanoma to Targeted Therapy with Kinase Inhibitorsen
dc.typeArtigo
unesp.author.orcid0000-0001-5816-9210[1]
unesp.author.orcid0000-0003-3775-3797[3]
unesp.author.orcid0000-0003-0342-8726[4]
unesp.author.orcid0000-0003-2735-1217[5]
unesp.campusUniversidade Estadual Paulista (Unesp), Faculdade de Medicina, Botucatupt
unesp.departmentCirurgia e Ortopedia - FMBpt

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Botucatu - FMB - Faculdade de Medicina