TMET-39. Metabolic Dissection of Leptomeningeal Metastasis

Abstract Leptomeningeal metastasis (LM) describes the metastatic dissemination of cancer cells to the cerebrospinal fluid (CSF)-filled compartment between the pia and arachnoid mater. The CSF, produced by the choroid plexus, is a hostile microenvironment deficient in nutritional content, that requires cancer cells to undergo metabolic adaptations to survive, grow, and take over the space. Indeed, LM causes brisk morbidity and mortality; a reflection of our poor mechanistic understanding of this disease. The central nervous system (CNS) is highly dependent on glucose as a source of energy. Similarly, cancer cells catabolize glucose to support proliferation, particularly in hypoxic microenvironments. Given that the CSF is hypoxic relative to serum, we hypothesized that glycolysis is a critical mechanism for LM progression. Interestingly, immunofluorescence staining shows that in the setting of LM, expression of glucose transporter 1 (GLUT1) is increased in choroid plexus epithelial cells. Furthermore, bulk RNA-sequencing of LM cells in the CSF demonstrates an upregulation of glycolytic enzymes, supporting a mechanism where LM cells disrupt CNS glucose homeostasis and rewire metabolic gene expression to expand in the CSF. To address this hypothesis, we investigated consequences of impaired glycolysis in LM models through CRISPR-Cas9-mediated deletion of lactate dehydrogenase A (LDHA-KO); an enzyme critical for glycolytic flux. In vitro, LDHA-KO cells proliferate at a similar rate to controls, however upon inoculation into the CSF of mice, LDHA-KO cells exhibit decreased tumor growth and improved survival, suggesting that glucose metabolism is implicated in LM progression. We have characterized the metabolic, transcriptional, and epigenetic consequences of LDHA perturbation in vitro and in vivo. Collectively, this work sheds light on the underappreciated metabolic landscape of LM and the homeostatic mechanisms of cancer cells in the CSF. By characterizing LM metabolic vulnerabilities, we will stratify molecular targets for the management of LM, which remains an unmet clinical need.