UV-Induced Epigenetic Changes in the Epidermis in Promoting Melanoma

Melanoma is an aggressive type of skin cancer with a low survival rate when it metastasizes. Melanoma originates mainly in sun-exposed areas, likely due to damage from sun ultraviolet (UV) irradiation. Sun UV radiation is a well-known human carcinogen that can damage DNA, and melanoma often originates in melanocytes with sun-damaged DNA. We have identified a new way that UV might contribute to melanoma formation, independent of direct DNA mutations in melanocytes. Our preliminary studies showed that the UV-induced environment in which melanocytes exist in the skin could change their behavior and even promote melanoma formation. We showed that epidermal cells, the neighboring cells of melanocytes in the skin, play a crucial role in setting up this environment. We identified that, upon exposure to UV irradiation, epidermal cells start to express and secrete proteins that alter the behavior of melanocytes. We showed that expression of these secreted proteins is typically inhibited by a complex of proteins called the Polycomb repressor complex, which functions to prevent melanocyte activation and suppress melanoma formation. UV irradiation, however, leads to the loss of Polycomb expression in epidermal cells resulting in the expression of secreted proteins that promote atypical melanocyte behavior. Interestingly, by studying human melanoma samples, we were able to detect the reduction of the Polycomb complex in the epidermis near melanoma sites.  Based on our preliminary studies, we propose a paradigm-shifting hypothesis that UV induces changes in epidermal cells to create an environment that promotes melanoma formation. We will test this hypothesis by addressing two specific aims. In Aim 1, we will use mouse models of melanoma to explore how losing Polycomb in the epidermis affects melanoma tumor formation and progression. These studies will establish the connection between Polycomb function in the epidermis and melanoma tumorigenesis. In Aim 2, we will use human primary melanoma samples to perform cellular studies to uncover the secreted proteins that alter melanocyte behavior and lead to melanoma. These studies will identify the signaling pathways by which the epidermis cross-talks with melanocytes during melanoma formation. In the long term, our discoveries will open new possibilities for preventative research focused on targeting epidermal cells.