Abstract IA009: Rewiring the CNS Niche: GABA Metabolic Plasticity and Blood–CSF Barrier Dynamics in Brain Metastasis

Abstract Brain metastasis remains one of the most devastating and lethal consequences of systemic cancer, yet the earliest stages of central nervous system (CNS) adaptation are still incompletely defined. Emerging principles in cancer neuroscience indicate that metastatic cells do not merely invade the brain—they co-opt neural signaling networks to enable survival and expansion within this highly specialized environment. Our work examines how neurotransmitter dynamics, particularly gamma-aminobutyric acid (GABA), reshape the metastatic niche in both brain parenchyma and leptomeninges. Rather than acting as passive recipients of neuronal cues, tumor cells undergo functional and metabolic adaptation that allows them to exploit local neurotransmitter pools. A key observation is that GABA levels are elevated within the metastatic brain microenvironment and cerebrospinal fluid (CSF), supporting tumor persistence in what is otherwise a metabolically restrictive setting. In this context, GABA functions not only as a signaling mediator but also as a bioenergetic substrate, linking neurotransmission to metabolic flexibility and growth advantage. Importantly, our findings identify the choroid plexus and blood–cerebrospinal fluid barrier (BCSFB) as active contributors to this process. While the blood–brain barrier (BBB) has traditionally been the focus of metastatic research, the choroid plexus emerges as a critical, underrecognized interface that shapes the CSF microenvironment. Tumor–choroid plexus crosstalk appears to modify local neurotransmitter handling, increasing GABA availability and fostering conditions that support metastatic colonization and leptomeningeal dissemination. Collectively, these data support a model in which metastatic “seed” cells dynamically recondition the CNS “soil” by altering neurotransmitter metabolism and engaging barrier-associated biology. In this view, brain metastasis is not simply a matter of invasion and permeability, but a process of neurochemical adaptation and metabolic rewiring within the neural ecosystem. Neurotransmitters serve as trophic and metabolic factors that directly fuel progression, and the choroid plexus–CSF axis functions as an active architect of the metastatic niche. By integrating neural signaling, metabolic plasticity, and CNS barrier dynamics, this work reframes brain metastasis as a disease of maladaptive neural integration and highlights tumor–neural–barrier interactions as promising translational targets at the convergence of oncology and neuroscience. Citation Format: Josh Neman. Rewiring the CNS Niche: GABA Metabolic Plasticity and Blood–CSF Barrier Dynamics in Brain Metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr IA009.