Cellular senescence drives skin carcinogenesis

Squamous cell carcinoma (SCC) is the second most common non-melanoma skin cancer, and has a high rate of recurrence and metastasis. Systemic genotoxic chemotherapeutic drugs such as doxorubicin (Doxo) can be used to treat SCC, but these agents can have deleterious long-term side effects, including fueling the development of more aggressive cancers. Some of the adverse effects of genotoxic chemotherapies might be due to their ability to induce cellular senescence. Cellular senescence is a tumor suppressive mechanism that entails a permanent cell growth arrest accompanied by several metabolic changes. Senescent cells increase during aging, and accumulating evidence suggests they can contribute to a variety of age related pathologies, including cancer, by secreting numerous pro-inflammatory molecules, growth factors and proteases, a feature termed the senescence-associated secretory phenotype (SASP). We recently showed that genotoxic and cytotoxic chemotherapeutic agents induce senescence and a SASP in vivo. However, a direct role for senescent cells in skin carcinogenesis in vivo remains unexplored. To investigate the role of senescent cells and the SASP in squamous cell skin carcinogenesis, we first induced senescence with Doxo in p16-3MR transgenic mice. These mice are designed to permit the selective elimination of senescent cells expressing the established senescence marker p16INK4a (p16) by administrating ganciclovir (GCV) which has a high affinity for the herpes simplex viral thymidine kinase (HSV-TK). Phosphorylated GCV is a DNA chain terminator that kills HSV-TK expressing cells by apoptosis. After Doxo treatment, we initiated skin SCC in p16-3MR mice with 7, 12-dimethylbenz[a]anthracene (DMBA), followed by treatment with 12-O-Tetradecanoylphorbol-13-acetate (TPA) to promote skin carcinogenesis. 25 weeks after Doxo treatment, we observed a significant increase in p16 mRNA levels as well as an increase in expression of the SASP factors IL-1α, MMP-9, and IL-17 in the skin of Doxo- compared to PBS- treated mice. Further, the presence of senescent cells resulted in significantly larger and more proliferative tumors compared to PBS-treated mice. Importantly, systemic elimination of Doxo-induced senescent cells using GCV reduced the expression of SASP factors and significantly reduced tumor size, suggesting that senescent cells fuel skin tumor progression. These findings will help our understanding of the role of chemotherapy-induced cellular senescence in skin carcinogenesis and will pave the way for developing novel therapeutics against squamous cell carcinoma and the deleterious side effects of genotoxic chemotherapies. Citation Format: Fatouma Alimirah, Alexis Valdovinos, Emily Chang, Sena Alptekin, Tanya Pulido, Elijah Jones, Chandani Limbad, Michael Velarde, Marco Demaria, Albert Davalos, Judith Campisi. Cellular senescence drives skin carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 466.