DSG2 synergizes with hedgehog signaling to promote skin tumor development
Basal cell and squamous cell carcinomas (BCC, SCC) are the most commonly diagnosed cancers in the United States. BCC are the result of aberrant activation of the canonical Hedgehog (Hh) pathway, typically via loss of function of the tumor suppressor Patched1 resulting from UV exposure. Hh signaling in SCC is less well understood. Treatment for both SCC and BCC is typically surgical resection; however, more advanced disease requires alternative approaches. Vismodegib, a small molecule inhibitor of the Hh pathway, is approved for use in advanced BCCs. However, major adverse effects and acquired drug resistance limit the effectiveness of this therapy. Identifying additional therapeutic targets may allow for more effective treatment. We previously reported that Desmoglein 2 (Dsg2), a desmosomal cadherin, is overexpressed in skin malignancies. Interestingly, Dsg2 expression corresponds with Gli1, a marker of canonical Hh activity, in both normal skin and tumors. Furthermore, we have demonstrated that Dsg2 enhances squamous tumor development and dysregulates signaling cascades that intersect with the Hh pathway. Here we cross the Ptc1+/lacZ reporter mouse, a model that mimics the familial form of BCC (Gorlin syndrome), with transgenic mouse models overexpressing Dsg2 in differential cell compartments of the epidermis, to assess the role of Hh-Dsg2 crosstalk in BCC and SCC development. Our results indicate that Dsg-Hh pathway interplay has a limited role in SCC development, but demonstrates that Hh and Dsg2 synergize to promote BCC formation. Immunohistochemical analysis of lesions, combined with in vitro approaches, implicate Stat3 as a mediator of this effect. Finally, we establish that concurrent inhibition of both Stat3 and Hh pathways is more effective at reducing Gli1 expression and tumor cell viability than targeting either pathway individually. The results here have implications for the clinical treatment of BCC, and by extension other Hh-dependent malignancies in which Stat3 signaling is deregulated.
Molecular biology|Cellular biology|Biogeochemistry
Brennan-Crispi, Donna, "DSG2 synergizes with hedgehog signaling to promote skin tumor development" (2015). ETD Collection for Thomas Jefferson University. AAI3731858.