Extracellular vesicles (EVs) constitute a vital component of intercellular communication,
exerting significant influence on metastasis formation and drug resistance mechanisms.
Malignant melanoma (MM) is one of the deadliest forms of skin cancers, because of
its high metastatic potential and often acquired resistance to oncotherapies. The
prevalence of BRAF mutations in MM underscores the importance of BRAF-targeted therapies,
such as vemurafenib and dabrafenib, alone or in combination with the MEK inhibitor,
trametinib. This study aimed to elucidate the involvement of EVs in MM progression
and ascertain whether EV-mediated metastasis promotion persists during single agent
BRAF (vemurafenib, dabrafenib), or MEK (trametinib) and combined BRAF/MEK (dabrafenib/trametinib)
inhibition.Using five pairs of syngeneic melanoma cell lines, we assessed the impact
of EVs - isolated from their respective supernatants - on melanoma cell proliferation
and migration. Cell viability and spheroid growth assays were employed to evaluate
proliferation, while migration was analyzed through mean squared displacement (MSD)
and total traveled distance (TTD) measurements derived from video microscopy and single-cell
tracking.Our results indicate that while EV treatments had remarkable promoting effect
on cell migration, they exerted only a modest effect on cell proliferation and spheroid
growth. Notably, EVs demonstrated the ability to mitigate the inhibitory effects of
BRAF inhibitors, albeit they were ineffective against a MEK inhibitor and the combination
of BRAF/MEK inhibitors. In summary, our findings contribute to the understanding of
the intricate role played by EVs in tumor progression, metastasis, and drug resistance
in MM.
