1. RAB27A promotes melanoma cell invasion and metastasis via regulation of pro-invasive exosomes.
- Author
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Guo D, Lui GYL, Lai SL, Wilmott JS, Tikoo S, Jackett LA, Quek C, Brown DL, Sharp DM, Kwan RYQ, Chacon D, Wong JH, Beck D, van Geldermalsen M, Holst J, Thompson JF, Mann GJ, Scolyer RA, Stow JL, Weninger W, Haass NK, and Beaumont KA
- Subjects
- Animals, Cell Line, Tumor, Cell Movement physiology, Clustered Regularly Interspaced Short Palindromic Repeats, Culture Media, Conditioned, Exosomes genetics, Gene Knockdown Techniques, HEK293 Cells, Humans, Melanoma genetics, Melanoma, Experimental genetics, Melanoma, Experimental metabolism, Melanoma, Experimental pathology, Melanosomes genetics, Melanosomes metabolism, Mice, Neoplasm Invasiveness, Nevus genetics, Nevus metabolism, Proteomics, Skin Neoplasms genetics, Skin Neoplasms metabolism, Skin Neoplasms pathology, Spheroids, Cellular, rab27 GTP-Binding Proteins biosynthesis, rab27 GTP-Binding Proteins genetics, Exosomes metabolism, Melanoma metabolism, Melanoma pathology, rab27 GTP-Binding Proteins metabolism
- 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., (© 2018 UICC.)
- Published
- 2019
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