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

Abstract

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.

Extracellular Vesicles-Based Biomarkers Represent a Promising Liquid Biopsy in Endometrial Cancer

“…Of note, regarding the other precipitation-based strategies analyzed in our study, the main advantage of ExoGAG technology is the purity of the EVs obtained, which is a key factor for their posterior characterization. Linked to the extensive literature showing that EVs derived from tumor cell lines contribute to tumor invasion, chemoresistance, angiogenesis, tumor innervation, metastasis or immune escape [21,22], and to those evidences demonstrating that tumor-derived EVs are associated with advanced disease in different indications [23][24][25][26][27][28] and the response to therapy [29], the analysis of EV-based biomarkers should be expedited for the translation of this form of liquid biopsy into the clinics.…”

Exosomes in Bone Sarcomas: Key Players in Metastasis

“…This transfer conferred an enhanced ability to metastasise and colonise other areas in mice models. In melanoma, cells expressing Rab27A produced exosomes packed with several proteins associated with a pro-invasive and motility phenotype, which upon uptake, increased the invasion capacity Rab27A-low melanoma cells [64]. This involvement of Rab27A in pro-metastatic changes was confirmed when knock-down of Rab27A in melanoma mice models resulted in decreased metastasis formation in vivo [64].…”

“…In melanoma, cells expressing Rab27A produced exosomes packed with several proteins associated with a pro-invasive and motility phenotype, which upon uptake, increased the invasion capacity Rab27A-low melanoma cells [64]. This involvement of Rab27A in pro-metastatic changes was confirmed when knock-down of Rab27A in melanoma mice models resulted in decreased metastasis formation in vivo [64]. In hepatocellular carcinoma, the uptake of exosomes from adherent hepatocellular carcinoma cells by detached cancer cells resulted in the release of adhesion-associated proteins and mRNA that induced the attachment of these cells, which was in turn associated with lung metastasis in vivo [65].…”

Extracellular Vesicles and Chemotherapy Resistance in the AML Microenvironment

“…On the other hand, Rab27 alpha and -beta (Rab27a/b) have both been identified as a critical modulators of EV biogenesis and secretion (39,88). Thus, blocking EV biogenesis via loss of Rab27a/b function (89) represents a potential therapeutic approach. The ultimate goal, of course, is not so much to suppress EV trafficking per se, but rather to exploit our understanding of EV biology to identify cellular targets to overcome chemoresistance and achieve sustained long-term remissions.…”