Medulloblastoma uses GABA transaminase to survive in the cerebrospinal fluid microenvironment and promote leptomeningeal dissemination
Vahan Martirosian, Krutika Deshpande, Hao Zhou, K. Robert Shen, Kyle Smith, Paul A. Northcott, Michelle Lin, Vazgen Stepanosyan, Diganta Das, Ján Remšík, Danielle Isakov, Adrienne Boire, Henk De Feyter, Kyle Hurth, Shaobo Li, Joseph L. Wiemels, Brooke Nakamura, Ling Shao, Camelia A. Danilov, Tai C. Chen, Josh Neman
Abstract
Medulloblastoma (MB) is a malignant pediatric brain tumor arising in the cerebellum. Although abnormal GABAergic receptor activation has been described in MB, studies have not yet elucidated the contribution of receptor-independent GABA metabolism to MB pathogenesis. We find primary MB tumors globally display decreased expression of GABA transaminase (ABAT), the protein responsible for GABA metabolism, compared with normal cerebellum. However, less aggressive WNT and SHH subtypes express higher ABAT levels compared with metastatic G3 and G4 tumors. We show that elevated ABAT expression results in increased GABA catabolism, decreased tumor cell proliferation, and induction of metabolic and histone characteristics mirroring GABAergic neurons. Our studies suggest ABAT expression fluctuates depending on metabolite changes in the tumor microenvironment, with nutrient-poor conditions upregulating ABAT expression. We find metastatic MB cells require ABAT to maintain viability in the metabolite-scarce cerebrospinal fluid by using GABA as an energy source substitute, thereby facilitating leptomeningeal metastasis formation.