Extracellular vesicles promote migration despite vemurafenib treatment in malignant melanoma cells

Abstract

Extracellular vesicles (EVs) were found to be one group of the determining factors in intercellular communication and have been shown to have a crucial role in metastasis formation and drug resistance. Malignant melanoma (MM) is one of the deadliest forms of skin cancers, because of its high metastatic potential and often acquired resistance to oncotherapies. BRAF mutation is the most prevalent genetic aberration in MM, which implicates BRAF (e.g. vemurafenib) or combined BRAF/MEK inhibitor therapy. Herein, we analyzed the role of EVs in MM progression and investigated if EVs can maintain their role in metastasis promotion during vemurafenib treatment. Five pairs of syngeneic melanoma cell lines were treated with EVs isolated from their or their pair’s supernatant. EVs’ impact on melanoma cells’ proliferation was investigated using cell viability and spheroid growth assays. Furthermore, to investigate changes in cell migration, mean squared dis-placement (MSD) and total travelled distance (TTD) were calculated based on video microscopy measurements and single cell tracking. In most of the cases, EV treatments did not affect cell proliferation and spheroid growth, however, their migration-promoting role was more prominent. Additionally, EVs originating from more resistant cells could counteract the inhibitory effect of vemurafenib. In conclusion, our findings provide further details to understand the complex role of EVs in tumor promotion, progression and single-agent vemurafenib resistance in MM.