University of Kentucky Center for Cancer and Metabolism (Pilot Project - Dr. John D'Orazio)

The cAMP signaling pathway is an attractive translational target as a UV- and melanoma-preventive strategy because it promotes melanocyte differentiation and genomic stability, positioning cells to resist UV mutagenesis and carcinogenic transformation. Individuals with inherited deficiencies in the melanocortin signaling axis have blunted cAMP responses in their melanocytes and are at high risk for melanoma as a result. Using an animal model that mimics the fair-skinned human, we found that induction of cAMP in the skin protects against UV damage by inducing melanin and by enhancing clearance of UV-induced DNA lesions. In order to develop cAMP induction as a translational strategy, however, we must understand its broader impact of topical cAMP induction on melanocyte physiology and cutaneous metabolism. We have evidence that cAMP signaling activates the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway in melanocytes. Because the mTOR pathway controls many aspects of cellular metabolism, we are interested in understanding the downstream effects of cAMP and mTOR signaling on melanocyte metabolism, UV resistance and genomic stability. Hypothesizing that cAMP promotes genomic stability by enhancing cellular energetics and increasing metabolites needed for UV resistance and DNA repair, we propose stable isotope- resolved metabolomics (SIRM) experiments using skin samples from our unique mouse model of the fair- skinned human to define metabolic networks linking cAMP signaling to pigmentation and UV damage repair. Determining how cAMP signaling affects melanocyte metabolism and to the broader metabolic landscape of the skin is critical to understanding how relevant metabolic pathways influence melanocyte genomic stability, UV mutagenesis and tumor progression.