Abstract 1361: Astrocytes activate neuronal programming in melanoma brain metastases

Abstract Melanoma Brain Metastases (MBM) pose a major challenge for treating metastatic melanoma. Up to 70% of advanced melanoma patients develop MBM, resulting in significant morbidity and mortality. Melanocytes, the originating cell type of melanomas, are derived from neural crest cells in development. Melanoma’s proclivity to metastasize to the brain has been anecdotally connected to its neural crest origins. Recently, transcriptomic analyses have demonstrated that MBM express a neuronal-like phenotype, upregulating neural crest factors such as NCAM (Neural cell adhesion molecule), L1CAM (L1 cell adhesion molecule protein), while expressing melanocytic markers like MITF (melanocyte induction transcription factor). The activation of neuronal development programming may be a key mediator in brain-metastatic growth, and thus necessitates a better understanding of how melanoma cells adapt to the brain. Astrocytes have emerged as the major host cell type that cancer cells encounter and interact with during brain metastasis formation. Typically, astrocytes regulate brain homeostasis and support neuronal function. Their response to injury, termed reactive astrocytosis, is a process defined by increased secretion of growth factors and inflammatory cytokine production. Post-mortem analyses of MBM patients reveal perilesional reactive astrocytosis. Here we demonstrate that astrocyte reactivity promotes MBM growth, using in vitro and in vivo model systems. We identify that astrocytes secrete factors that increase tumor growth and expression of neural development factors. Moreover, pharmacological inhibition of neural development pathways, like Wnt signaling, attenuate the effects of astrocyte secreted factors. We developed a brain adapted melanoma line, D4M3a BrJ, and demonstrate the time course of astrocyte reactivity in vivo in its relationship with tumor growth. Our findings provide evidence that astrocyte reactivity promotes MBM growth and activation of neural development programming, unveiling a new therapeutic avenue for targeting the brain metastatic niche. Citation Format: Julia K. Farnan, Maria R. Cavallo, Edward J. Hartsough, Joshua G. Jackson. Astrocytes activate neuronal programming in melanoma brain metastases [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 1361.