This risk of a mole transforming into melanoma is a concern for many individuals. This is particularly true for soldiers in the army who are exposed to high levels of sunlight, an environmental factor known to promote melanoma formation. Indeed, clinical studies suggest a substantial percentage of melanoma may arise from moles (Nevi). How can we prevent such a transition? First, we need to fully delineate the processes of melanocytes changing into nevi and then melanoma. This is not feasible to achieve by only examining biopsied human skin containing melanoma, as it is not possible to retrospectively determine the histopathology of such melanoma when they were in the form of benign nevi. In Aim1, we will establish a preclinical mouse model where we can predictably induce nevi formation in the skin epidermis, where melanoma typically arise, to trace their fate into melanoma in a well-controlled experimental setting. We have identified a novel research tool in the melanoma research field to introduce a mutation (BrafV600E), known to cause nevi formation in melanocytes in mouse skin. After we irradiate the skin with ultraviolet-B (UVB) to mimic sun exposure, we will harvest the skin at different time points to trace changes in gene expression in melanocytes and surrounding cells (epithelial cells and immune cells) using a variety of techniques including skin tissue section analyses and single cell RNA sequencing (scRNA seq). We will then examine human nevi and melanoma skin sections to understand how our findings are relevant to understanding nevi-melanoma transition in humans. In Aim2, we aim to establish an initial paradigm for studying how therapeutic interventions can effectively preclude nevi from forming melanoma. We will test how established immunotherapeutic drugs can influence melanoma formation from nevi using our mouse model. This will allow future studies to broadly exploit our model to identify the minimal dosages or combinations of drugs that may prevent melanoma beyond immunotherapy.