Abstract IA014: The role of aging in reactivation from metastatic melanoma dormancy
Authors: Fane Mitchell , Chhabra Yash , Alicea Gretchen , Zabransky Daniel , Hüser Laura , Maranto Devin , Aguirre-Ghiso Julio , Weeraratna Ashani 
Published: January 2023

Abstract
Disseminated cancer cells (DCCs) that escape the primary site can seed in distal tissues, but may take several years, or even decades to grow out into overt metastases, a phenomenon termed tumor dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully model or characterize dormancy within melanoma. Our previous data has indicated that while tumors grow more slowly in aged mouse skin, they form more aged lung metastases. We have previously shown that dermal fibroblasts were key drivers of age-related changes in the skin to promote a more aggressive melanoma phenotype. A model of melanoma progression that addresses these microenvironmental complexities is the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state. We queried whether the lung microenvironment undergoes similar age-related changes that provide a permissive niche for metastatic outgrowth. Our new data identified that while Wnt5A and AXL are required for efficient dissemination from the primary tumor towards metastatic tissues, they act as master regulators of activating melanoma dormancy within the lung. The young lung microenvironment maintains this dormant melanoma state; however, age induced reprograming of lung fibroblasts increases their secretion of the soluble Wnt antagonist sFRP1, which inhibits both Wnt5A and AXL to enable reactivation from dormancy and the formation of larger metastatic colonies in the aged lung. We find that downregulation of AXL in melanoma cells leads to an increase in the related TAM family receptor MERTK, which promotes a proliferative melanoma phenotype, enables reactivation from dormancy and induces efficient metastatic outgrowth in aged models. Follow up data from these models highlights decreases in immune infiltration of CD4+ and CD8+ T-cells, which appears to be partially mediated by an increase in secretion of Arginase-1 (ARG1) from aged lung fibroblasts. Further, we find that aged lung fibroblasts secrete CXCL1 which promotes infiltration of immunosuppressive T-regulatory cells and Myeloid Derived Suppressive Cells. Finally, we see dramatic changes in extracellular matrix secretion and remodeling from young vs aged lung fibroblasts, which alters in vitro melanoma growth to promote dormancy in melanoma cells grown on young lung fibroblast ECM. Overall, we find that a plethora of age-related changes in metastatic microenvironments such as the lung contribute to an increase in melanoma progression relative to younger niches. This not only provides novel tools to assess metastatic dormancy in melanoma, which is critically understudied due to a lack of pre-clincal in vitro and in vivo models, but also necessitates the idea that age needs to be considered in pre-clinical modelling of age-related cancers such as melanoma, where the median age of diagnosis is 63, and when there is a clear increase in incidence, mortality and metastasis within geriatric patients.
Citation Format: Mitchell Fane, Yash Chhabra, Gretchen Alicea, Daniel Zabransky, Laura Hüser, Devin Maranto, Julio Aguirre-Ghiso, Ashani Weeraratna. The role of aging in reactivation from metastatic melanoma dormancy [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA014.