Roles of senescence in the response of the skin to UV radiation and in early tumorigenesis

Skin cancer, the most common cancer worldwide, is primarily driven by prolonged exposure to ultraviolet (UV) radiation. UV radiation induces various cellular responses, including DNA damage, cell cycle arrest, apoptosis, and senescence, which collectively impact tissue integrity and cancer risk. Senescence is a cellular state of irreversible growth arrest, marked by upregulation of key biomarkers, including cyclin-dependent kinase inhibitors, as well as SA-β-gal activity, and the acquisition of a secretory phenotype, termed the senescence-associated secretory phenotype (SASP). It is a double-edged sword in tumorigenesis: while it prevents damaged cells from proliferating, it also fosters a pro-tumorigenic microenvironment. Emerging therapeutic strategies, such as senolytics, aim to selectively target senescent cells or block their detrimental activities. These offer new avenues for modulating these responses and potentially preventing or treating skin cancer. The dynamics of UV-induced senescence in the skin and its contribution to tumor initiation remain poorly understood. My goal is to address the formation dynamics and functions of UV-induced senescent cells in the skin, and investigate whether could senolytic treatments mitigate these effects?

In this study, we exposed mice to UV radiation and tracked senescent cells in the epidermis and dermis using markers such as p21 and SA-β-gal. Our results show that p21+ cells initially appear in both layers, they accumulate in the dermis over time but gradually disappear from the epidermis. To evaluate therapeutic strategies, we treated a subset of UV-exposed mice with the senolytic drug ABT-199, which significantly reduced the number of senescent cells in the dermis. This reduction was accompanied by a decrease in inflammatory markers, suggesting that senolytics can mitigate the detrimental effects of senescence. Moving forward, I will further investigate the molecular pathways linking senescence to tumor initiation and the therapeutic efficacy of senolytics in reducing UV induced inflammation and tumorigenesis.

Collectively, this research sheds light on the dynamics of UV-induced senescence in the skin, its role in inflammation and tumorigenesis, and the therapeutic potential of senolytic treatments. By enhancing our understanding of these processes, this work provides a foundation for developing innovative strategies to prevent UV-induced skin cancer.