Characterization of UVA induced metabolic changes in melanoma in vitro and in vivo and identification of therapeutic targets

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Ultraviolet A (UVA) (¿>320nm) radiation is known to contribute to the initiation of melanoma, but the role of UVA in the progression of melanoma is still unknown. In previous work, we could show that repetitive UVA irradiation increases glucose consumption and lactate production (Warburg effect). Increased lactic acid production, in turn, induces expression of matrix metalloproteinases (MMP) by melanoma cells and enhances their invasive potential. We hypothesize, that UVA induced metabolic changes are functionally relevant for melanoma progression and inhibition thereof may impede melanoma progression. Therefore, in collaboration with partners of this consortium, metabolic changes induced by repetitive UVA irradiation will be investigated in vitro in melanocytes and melanoma cells and in vivo in murine melanoma models. Identification of UVAinduced metabolic changes (in glycolysis, urea cycle, pentose phosphate pathway, citrate cycle, amino acid metabolism, fatty acid and cholesterol synthesis, and other pathways) will enable the selection of specific inhibitors of metabolic key enzymes. These inhibitors against key enzymes of UVA-induced metabolic changes will be applied topically or systemically in murine melanoma models to investigate their effect on melanoma progression in vivo.In addition histological melanoma specimens will be screened for established quantitative marker mutations to quantify individual UVA exposure history and key enzymes as indicators for UVAinduced metabolic changes will be immunohistologically detected and correlated to the amount of UVA exposure. This work will help to clarify the role of UVA induced metabolic changes and respective inhibitory strategies during progression of melanoma.