Dsg2 Enhances Oncogenic Cellular Signaling in an Autocrine and Paracrine Manner

Non-melanoma skin cancers—basal and squamous cell carcinomas (BCC & SCC, respectively)—are the most commonly diagnosed malignancies worldwide. Both cancers are mostly indolent, but discerning the molecular and cellular pathways altered in advanced cases is critical to designing more efficacious therapeutics. The desmosomal cadherin desmoglein 2 (Dsg2) mediates cell-cell adhesion in cardiac and epithelial tissues, including the skin, and helps maintain tissue integrity against mechanical stress. Intriguingly, though loss of cell-cell adhesion is a common feature of tumorigenesis, Dsg2 expression is upregulated in BCCs and SCCs. We have previously shown that Dsg2 can promote squamous neoplasia in the skin. Here, the mechanisms underlying oncogenic signaling modulated by Dsg2 were explored. Dsg2 positively influenced autocrine signaling in malignant keratinocytes by promoting EGFR and c-Src activation and leading to increased cellular proliferation and migration. In addition, Dsg2 promoted paracrine signaling by promoting the secretion of extracellular vesicles from SCC cells and enhancing the transfer of pro-mitogenic factor from the cancer cells to fibroblasts. Dsg2 enhanced SCC tumor xenograft growth in vivo through both autocrine activation of mitogenic pathways in the cancer cells and stimulating angiogenesis in the tumor through paracrine signals. Targeting Dsg2 in the xenografts with a monoclonal antibody inhibited both cancer cell proliferation by inhibiting autocrine activation of EGFR and c-Src and tumor angiogenesis by attenuating the paracrine secretion of pro-angiogenic PDGF-BB. Finally, Dsg2 overexpression in the basal keratinocytes of transgenic mice enhanced cutaneous wound healing by stimulating keratinocyte growth, migration, and enhanced expression and secretion of cytokines including the urokinase-type plasminogen activator receptor (uPAR) which plays a critical role in migration and metastasis. This work illustrates a multi-dimensional role for Dsg2 in modulating epidermal and tumor-associated signaling and lays the groundwork for further development and characterization of novel therapeutics targeting Dsg2 for SCC treatment