LAUSR

Melanoma is the deadliest form of skin cancer, with its incidence rising disproportionally to other cancers. Chronological aging is a major risk factor in all types of cancer as it has been shown to drive changes in noncancerous cells (stromal and immune) of the tumor microenvironment (TME) to promote tumor initiation and progression. Ultraviolet radiation (UVR) exposure, which is a major risk factor for melanoma, also can cause a physical premature aging phenotype, known as photoaging. Photoaging of the skin often occurs in tandem with chronological aging, and contributes to the physical features of aging through similar alterations in normal skin structure (eg. collagen degradation). However, the molecular mechanisms of how photoaging compares to chronological aging in changing the TME and on tumor progression is still lacking.Preliminary data have indicated that photoaging of young dermal fibroblasts induce some similar signature changes to that of intrinsically aged. We have shown in-vitro that UVA exposure in young fibroblasts cause upregulation in MMP-1, a matrix remodeling protein, and downregulation in β-catenin, the cell adhesion transcription regulator. These same changes were also shown in chronologically aged fibroblasts. In addition, both photoaging and chronological aging decreases ECM structural integrity, with increased collagen fragmentation and a reduction in the renewal of cross-linking proteins. To investigate how photoaging contributes to the pro-tumorigenic microenvironment of the aged dermis, we are using biochemical and phenotypic assays to study how chronic UVA exposure induces an intrinsically aged-like fibroblast behavior and secretome. We also hypothesize that photoaged fibroblasts reprogram the TME to become more permissible for the growth of tumor cells, and will test changes in invasion and metastasis or melanoma both in-vitro and in-vivo.Studying the impact of photoaging on aging in the skin microenvironment will help identify therapeutic targets and have direct clinical applications for cancer patients. Citation Format: Vania Wang, Yash Chhabra, Laura Hueser, Sneha Pramod, Alexis Carey, Ashani Weeraratna. Extrinsic photoaging vs intrinsic aging in dermal fibroblasts: Its impact on the microenvironment and melanoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1274.