Dsg2 increases exosome release and enhances EGFR/c-Src content: A mechanism for intercellular mitogenic effect
Andrew M. Overmiller; Jennifer A. Pierluissi; Peter J Wermuth; Ubaldo E. Martinez-Outshoorn, MD; Madalina Tuluc; Adam J. Luginbuhl; Joseph Curry; Larry A. Harshyne; James K. Wahl, III; Andrew P. South; and M G Mahoney
Exosomes are nanoscale membrane-derived vesicles that are secreted by cancer cells and play a critical role in modulating the tumor microenvironment and disease pathogenesis. Dsg2, a desmosomal cadherin often overexpressed in skin malignancies including squamous cell carcinoma (SCC), can activate EGFR/c-Src signaling and promote oncogenesis. We sought to address the potential role of Dsg2 in exosome biogenesis and intercellular signaling in SCC. Here, purified exosomes from SCC cells and head/neck SCC patient sera were enriched with a processed 65 kDa membrane-associated C-terminal fragment of Dsg2. Cells overexpressing Dsg2 had increased exosome release and protein content and produced particles enriched with EGFR/c-Src, enhancing proliferation in recipient fibroblasts, compared to parental cell exosomes. This study suggests a mechanism by which SCC cells can promote intercellular signaling and modulate the tumor microenvironment through enhanced Dsg2 levels.