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

已知紫外线A (UVA)（¿>320nm）辐射有助于黑色素瘤的发生，但UVA在黑色素瘤进展中的作用仍不清楚。在之前的工作中，我们可以证明重复的UVA照射会增加葡萄糖消耗和乳酸生成（Warburg效应）。乳酸生成的增加反过来诱导黑色素瘤细胞表达基质金属蛋白酶（MMP），并增强其侵袭潜力。我们假设，UVA诱导的代谢变化在功能上与黑色素瘤的进展有关，抑制这种变化可能会阻碍黑色素瘤的进展。因此，与该联盟的合作伙伴合作，将在体外研究重复UVA照射在黑色素细胞和黑色素瘤细胞以及小鼠黑色素瘤模型中引起的代谢变化。确定uv诱导的代谢变化（糖酵解、尿素循环、戊糖磷酸途径、柠檬酸循环、氨基酸代谢、脂肪酸和胆固醇合成等途径）将有助于选择代谢关键酶的特异性抑制剂。这些针对uva诱导代谢变化的关键酶的抑制剂将局部或全身应用于小鼠黑色素瘤模型，以研究它们对体内黑色素瘤进展的影响。此外，将对组织学黑色素瘤标本进行筛选，以确定已建立的定量标记突变，以量化个体UVA暴露史，并将免疫组织学检测作为UVA诱导代谢变化指标的关键酶，并将其与UVA暴露量相关联。这项工作将有助于阐明UVA诱导的代谢变化的作用和各自的抑制策略在黑色素瘤的进展。

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.