Abstract

miRNA- and Cytokine-Associated Extracellular Vesicles Mediate Squamous Cell Carcinomas

My Mahoney, Professor and Vice Chair, Thomas Jefferson University

Extracellular vesicles (EVs) serve as intercellular messengers carrying lipids, proteins, and genetic material that have been shown to play a significant role in many pathological conditions, including cancer. We recently demonstrated that the cadherin desmoglein 2 (Dsg2), a stem cell marker upregulated in many cancers, modulates EV biogenesis in squamous cell carcinomas (SCCs). Here, we show that this process occurs through the endocytic pathway and requires membrane association through protein palmitoylation. In SCC xenograft models, tumor size correlated with EV release and co-treatment with EVs increased xenograft size. To assess the molecular messengers contributing to the pathogenicity of Dsg2-mediated EVs, a cytokine antibody array was employed to show that Dsg2 stimulates release of multiple cytokines known to promote angiogenesis and inflammation, both of which enhance tumor growth. Profiling by RNAseq showed dramatic down-regulation of miRNAs that target those cytokines. These results suggest that intercellular communication through cell-cell adhesion, cytokine release, and secretion of extracellular vesicles are coordinated, critical for tumor growth and development.