Abstract

Modulation of Extracellular Vesicle Release and Content in SCC Cells

My Mahoney, Professor and Vice Chair, Thomas Jefferson University

Emerging as critical in the pathobiology of cancer are nanosized extracellular membrane vesicles (EVs) secreted by tumor cells into the blood and other bodily fluids carrying molecular constituents to modulate local and distant tumor microenvironment. EVs can be taken up by recipient cells and can modulate diverse biological processes including cell polarity and tissue morphogenesis and represent novel and valuable circulating biomarkers for tumor prognosis and diagnosis. Thus, defining factors that affect the release or modify the content of EVs is critical to our understanding of not only normal tissue development but also malignant transformation and progression. We have shown that the cadherin desmoglein 2 (Dsg2), an important regulator of growth and survival signaling pathways, drives tumorigenesis in experimental models, and clinical samples confirm that Dsg2 is indeed overexpressed in those cancers. We observed that Dsg2 is enriched in EVs derived from SCC cells and patient sera. Dsg2 modulates EV release and mitogenic content including EGFR and c-Src. Dsg2-labeled EVs are taken up by dermal fibroblasts, activating Erk1/2 and Akt signaling and promoting cell proliferation. Our work thus far defines a mechanism by which cancer cells can modulate the tumor microenvironment, a step critical for tumor progression.