BRAF V600 inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells

The BRAF inhibitors vemurafenib and dabrafenib can be used to treat patients with metastatic melanomas harboring mutations. Initial antitumoral responses are often seen, but drug-resistant clones with reactivation of the MEK-ERK pathway soon appear. Recently, the secretome of tumor-derived extracell...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2017-07, Vol.114 (29), p.E5930
Main Authors: Lunavat, Taral R, Cheng, Lesley, Einarsdottir, Berglind O, Olofsson Bagge, Roger, Veppil Muralidharan, Somsundar, Sharples, Robyn A, Lässer, Cecilia, Gho, Yong Song, Hill, Andrew F, Nilsson, Jonas A, Lötvall, Jan
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Drug Resistance, Neoplasm
Extracellular Vesicles - drug effects
Extracellular Vesicles - genetics
Extracellular Vesicles - metabolism
Gene Expression Regulation, Neoplastic - drug effects
Humans
Indoles - pharmacology
Melanoma - drug therapy
Melanoma - genetics
Melanoma - pathology
Melanoma, Cutaneous Malignant
Mice, Inbred NOD
Microphthalmia-Associated Transcription Factor - genetics
Microphthalmia-Associated Transcription Factor - metabolism
MicroRNAs - genetics
MicroRNAs - metabolism
Mutation
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins B-raf - antagonists & inhibitors
Proto-Oncogene Proteins B-raf - genetics
Skin Neoplasms - drug therapy
Skin Neoplasms - genetics
Skin Neoplasms - pathology
Sulfonamides - pharmacology
Up-Regulation - drug effects
Vemurafenib
Xenograft Model Antitumor Assays
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The BRAF inhibitors vemurafenib and dabrafenib can be used to treat patients with metastatic melanomas harboring mutations. Initial antitumoral responses are often seen, but drug-resistant clones with reactivation of the MEK-ERK pathway soon appear. Recently, the secretome of tumor-derived extracellular vesicles (EVs) has been ascribed important functions in cancers. To elucidate the possible functions of EVs in -mutant melanoma, we determined the RNA content of the EVs, including apoptotic bodies, microvesicles, and exosomes, released from such cancer cells after vemurafenib treatment. We found that vemurafenib significantly increased the total RNA and protein content of the released EVs and caused significant changes in the RNA profiles. RNA sequencing and quantitative PCR show that cells and EVs from vemurafenib-treated cell cultures and tumor tissues harvested from cell-derived and patient-derived xenografts harbor unique miRNAs, especially increased expression of miR-211-5p. Mechanistically, the expression of miR-211-5p as a result of BRAF inhibition was induced by increased expression of MITF that regulates the TRPM1 gene resulting in activation of the survival pathway. In addition, transfection of miR-211 in melanoma cells reduced the sensitivity to vemurafenib treatment, whereas miR-211-5p inhibition in a vemurafenib resistant cell line affected the proliferation negatively. Taken together, our results show that vemurafenib treatment induces miR-211-5p up-regulation in melanoma cells both in vitro and in vivo, as well as in subsets of EVs, suggesting that EVs may provide a tool to understand malignant melanoma progression.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1705206114