Abstract 2559: The impact of aging on the brain microenvironment and melanoma brain metastasis: Vasculature dysfunction, inflammation, and tumor colonization

Abstract Melanoma is the third most common source of brain metastases after lung and breast cancer; however, melanoma has the highest risk of spreading to the central nervous system (CNS). Previous studies have shown that age is an independent negative prognostic factor for early-stage and metastatic melanoma. Our lab has shown differences in the skin, lung, and pancreatic aging microenvironment that affect older patients' prognosis and response to therapy and emphasizes the need to uncover other molecular mechanisms of cancer progression in older patients. Currently, the role of the aged brain microenvironment in the development of melanoma brain metastases (MBM) is poorly understood due to limited data available. We hypothesize that changes in the aged brain microenvironment create a more tumor-permissive environment for melanoma metastasis to the brain. Previous studies have shown that the native brain environment, particularly glial cells such as astrocytes and microglia, can directly interact with melanoma in both a pro- and anti-tumorigenic manner. Additionally, melanoma cells have been shown to disrupt the blood-brain barrier (BBB) during migration; however, whether the aging microenvironment makes the BBB more susceptible to this disruption is not clearly understood. To understand these factors, we employed various techniques, including in vitro primary culture of brain cells from young and aged mice, ex vivo brain co-cultures with melanoma, and in vivo mouse models to characterize the aging brain microenvironment. We have shown that the young and aged brain endothelium impacts melanoma migration and have observed differences in vascular integrity and vasculature changes with aging and tumor presence. Additionally, aged mice that are more prone to vasculature dysfunction have a higher rate of melanoma colonization in the brain and higher activation of pro-inflammatory factors from the native brain microenvironment. These results give insight into differences in melanoma migration and colonization in the brain between aged and young mice. However, whether this results from astrocyte involvement in melanoma recruitment or disruption of the blood-brain barrier remains to be elucidated. The knowledge from this study will be pivotal to shaping future work by analyzing molecular changes in young and aged patients with malignant melanoma. It may provide new therapeutic targets for effectively preventing and treating this disease. Citation Format: Cheyenne M. Palm, Alexis Carey, Murilo Ramos Rocha, Kevin Zhang, Ashani Weeraratna. The impact of aging on the brain microenvironment and melanoma brain metastasis: Vasculature dysfunction, inflammation, and tumor colonization. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2559.