RAB27A promotes melanoma cell invasion and metastasis via regulation of pro‐invasive exosomes.

Despite recent advances in targeted and immune‐based therapies, advanced stage melanoma remains a clinical challenge with a poor prognosis. Understanding the genes and cellular processes that drive progression and metastasis is critical for identifying new therapeutic strategies. Here, we found that the GTPase RAB27A was overexpressed in a subset of melanomas, which correlated with poor patient survival. Loss of RAB27A expression in melanoma cell lines inhibited 3D spheroid invasion and cell motility in vitro, and spontaneous metastasis in vivo. The reduced invasion phenotype was rescued by RAB27A‐replete exosomes, but not RAB27A‐knockdown exosomes, indicating that RAB27A is responsible for the generation of pro‐invasive exosomes. Furthermore, while RAB27A loss did not alter the number of exosomes secreted, it did change exosome size and altered the composition and abundance of exosomal proteins, some of which are known to regulate cancer cell movement. Our data suggest that RAB27A promotes the biogenesis of a distinct pro‐invasive exosome population. These findings support RAB27A as a key cancer regulator, as well as a potential prognostic marker and therapeutic target in melanoma. What's new? Although metastasis is the primary cause of death in melanoma, we still do not fully understand the molecular mechanisms involved. In this study, the authors found that a GTPase called RAB27A is overexpressed in a subset of melanomas, and correlates with poor survival. RAB27A appears to stimulate melanoma cells to secrete pro‐invasive exosomes, which enhance the motility, invasiveness, and metastasis of tumor cells. These results indicate that RAB27A overexpression may provide a useful prognostic biomarker, as well as a potential therapeutic target for inhibiting melanoma metastasis. [ABSTRACT FROM AUTHOR]