A Network of MicroRNAs and mRNAs Involved in Melanosome Maturation and Trafficking Defines the Lower Response of Pigmentable Melanoma Cells to Targeted Therapy
Author:
Vitiello Marianna12ORCID, Mercatanti Alberto1ORCID, Podda Maurizio Salvatore123ORCID, Baldanzi Caterina123, Prantera Antonella123, Sarti Samanta12ORCID, Rizzo Milena1ORCID, Salvetti Alessandra4ORCID, Conte Federica5ORCID, Fiscon Giulia56ORCID, Paci Paola56ORCID, Poliseno Laura12ORCID
Affiliation:
1. Institute of Clinical Physiology (IFC), National Research Council (CNR), 56124 Pisa, Italy 2. Oncogenomics Unit, Core Research Laboratory (CRL), ISPRO, 56124 Pisa, Italy 3. University of Siena, 53100 Siena, Italy 4. Unit of Experimental Biology and Genetics, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy 5. Institute for Systems Analysis and Computer Science “A. Ruberti” (IASI), National Research Council (CNR), 00185 Rome, Italy 6. Department of Computer, Control, and Management Engineering “A. Ruberti” (DIAG), Sapienza University of Rome, 00185 Rome, Italy
Abstract
Background: The ability to increase their degree of pigmentation is an adaptive response that confers pigmentable melanoma cells higher resistance to BRAF inhibitors (BRAFi) compared to non-pigmentable melanoma cells. Methods: Here, we compared the miRNome and the transcriptome profile of pigmentable 501Mel and SK-Mel-5 melanoma cells vs. non-pigmentable A375 melanoma cells, following treatment with the BRAFi vemurafenib (vem). In depth bioinformatic analyses (clusterProfiler, WGCNA and SWIMmeR) allowed us to identify the miRNAs, mRNAs and biological processes (BPs) that specifically characterize the response of pigmentable melanoma cells to the drug. Such BPs were studied using appropriate assays in vitro and in vivo (xenograft in zebrafish embryos). Results: Upon vem treatment, miR-192-5p, miR-211-5p, miR-374a-5p, miR-486-5p, miR-582-5p, miR-1260a and miR-7977, as well as GPR143, OCA2, RAB27A, RAB32 and TYRP1 mRNAs, are differentially expressed only in pigmentable cells. These miRNAs and mRNAs belong to BPs related to pigmentation, specifically melanosome maturation and trafficking. In fact, an increase in the number of intracellular melanosomes—due to increased maturation and/or trafficking—confers resistance to vem. Conclusion: We demonstrated that the ability of pigmentable cells to increase the number of intracellular melanosomes fully accounts for their higher resistance to vem compared to non-pigmentable cells. In addition, we identified a network of miRNAs and mRNAs that are involved in melanosome maturation and/or trafficking. Finally, we provide the rationale for testing BRAFi in combination with inhibitors of these biological processes, so that pigmentable melanoma cells can be turned into more sensitive non-pigmentable cells.
Funder
ISPRO-Istituto per lo Studio, la Prevenzione e la Rete Oncologica AIRC-Associazione Italiana per la Ricerca sul Cancro
Subject
Cancer Research,Oncology
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