LAUSR

Alpha-synuclein (α-syn; encoded by gene SNCA), which is an intrinsically disordered protein belonging to the synuclein family, is a common biological factor in Parkinson’s disease and melanoma. Aggressive melanomas express high levels of α-syn, but the precise biological role of this protein in melanoma progression is not known. Our group has previously reported that α-syn promotes the release of extracellular vesicles (EVs) and regulates the trafficking of transferrin receptor in melanoma cells. During our studies of exosomal/EV markers, we found that CD81 and CD9, two key members of the tetraspanin family, were significantly downregulated in SK-MEL-28 SNCA-knock out clones compared to control cells. In contrast, a robust upregulation of CD63, another tetraspanin protein, was observed in SNCA-KO cells, which might be due to a compensatory mechanism for the downregulation of CD81 and CD9. CD81 and CD9 have been proposed as potential therapeutic targets, and CD63 was proposed as a positive prognostic marker in melanoma in numerous studies. Our group has previously shown that knocking out α-syn causes decreased tumor growth in vivo and in vitro. We hypothesize that α-syn regulates the levels of these tetraspanins, possibly by sorting into heterogeneous multivesicular bodies and modulating the exosomal secretion and lysosomal degradation of these proteins. This might be one of the principal mechanisms by which α-syn promotes progression of melanoma. We also have initial evidence from transmission electron microscopy (TEM) that depletion of α-syn causes the morphological alterations of plasma-membrane structure in melanoma cells, and it is known that CD9, CD81 and CD63 are important transmembrane proteins involved in membrane organization. This is the very first report of α-syn as a regulator of cellular homeostasis of CD9, CD81 and CD63, and further work is needed to understand the underlying mechanism. Citation Format: Nirjhar Mandal Aloy, Michael W. Graner, Stephan N. Witt. Alpha-synuclein may promote melanoma progression by modulating the levels of tetraspanin proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1357.