Targeting UV-induced senescence in the skin microenvironment to prevent melanomagenesis

Summary: Abstract Body: Exposure to ultraviolet radiation (UV) and aging are the major risk factors for cutaneous melanoma (CM). The resulting accumulation of DNA damage is necessary but not sufficient for tumor formation, but the mechanisms by which skin aging and photoaging (UV) trigger a tumorigenic skin microenvironment (ME) are largely unknown. Here, we investigated the effects of UVB-induced senescence in non-tumor skin cells on CM progression, and the potential of senolytic drugs as therapeutics. First, we observed that implantation of B16 melanoma cells in mice pre-exposed to UVB yielded larger tumors with shorter latency, and a more suppressive immune infiltrate than in non-irradiated mice. Aging and UVB exposure resulted in similar, molecular and cellular changes in mouse skin, such as accumulation of senescence cells and expression of the senescence-associated secretory phenotype (SASP), increased inflammation and dermal remodeling, which were reverted by the pharmacological or genetic ablation of senescent cells, suggesting similar pro-tumorigenic mechanisms in aging and photoaging. To determine the effect of senescence in the skin on tumor growth, we exposed various mouse and human CM cell lines to the secretome of UV-induced senescent skin-derived keratinocytes and fibroblasts. These secretomes promoted CM cell growth, invasion and migration. Co-implantation of mouse melanoma cells (B16 or YUMM) and senescent dermal fibroblasts resulted in larger tumors compared to cell mixtures with non-senescent dermal fibroblasts. Lastly, the observed UV-related increase in tumor growth and immunosuppressive ME were significantly reduced by the elimination of UV-induced skin senescent cells using the genetic model or senolytics. Our findings suggest that accumulation of SASP expressing senescent cells in UVB-damaged skin promote melanoma growth, and that senolytics may restore a non-tumorigenic skin ME; thus, they may be a promising preventative and therapeutic approach for early intervention in CM. Danial Khayatan¹, Julian Zulueta¹, Arianna Kim¹, Rolando Perez-Lorenzo¹ 1. Dermatology, Columbia University, New York, NY, United States. Pigmentation, Melanoma, and Melanoma Immune Surveillance