Fsmp-03. investigating co-opted astrocytic metabolism in melanoma brain metastasis

Abstract Melanoma, an aggressive form of skin cancer, frequently metastasizes to the brain. While peripheral melanoma is largely treatable, MBM fail to respond to current therapeutics and is a clear unmet clinical need. Initial clinical symptoms of Melanoma Brain Metastases (MBM) typically include headaches, seizures and other neurological deficits, suggesting that MBM disrupt normal brain functions. One of the major cell types that melanoma encounter and interact with during brain metastasis are astrocytes. Astrocytes, the most abundant cell in the brain, interact with neurons and the vasculature, provide trophic and energetic support to neurons, and regulate local blood flow. Metabolic pathways in astrocytes, particularly the glutamate-glutamine cycle, are essential for the recycling and resupply of neurotransmitters needed to maintain the excitation/inhibition balance. We propose that MBM co-opt astrocytic metabolism, fueling MBM growth, and deplete metabolic intermediates crucial for neuronal activity leading to altered neurologic function. We begin to unravel the metabolic interactions between astrocytes and MBM using novel modeling platforms with genetic and pharmacological tools to manipulate the tumor microenvironment. This project investigates the contribution of astrocytic metabolism to MBM growth. We intend on dissecting the distinct metabolic needs of metastatic brain melanoma in the CNS microenvironment and the subsequent neurological consequences. Completion of this project will provide a platform to study MBM and interaction with the local brain microenvironment. Inhibiting metabolic interactions between melanoma and glial cells may provide new avenue for therapeutic targeting of MBM.