@article{ed0c79864e0f4154867e95e1be6e72e8,
title = "Medulloblastoma uses GABA transaminase to survive in the cerebrospinal fluid microenvironment and promote leptomeningeal dissemination",
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.",
keywords = "ABAT, GABA shunt, cerebrospinal fluid, leptomeningeal disease, medulloblastoma, oxidative phosphorylation, tumor dormancy, tumor microenvironment",
author = "Vahan Martirosian and Krutika Deshpande and Hao Zhou and Keyue Shen and Kyle Smith and Paul Northcott and Michelle Lin and Vazgen Stepanosyan and Diganta Das and Jan Remsik and Danielle Isakov and Adrienne Boire and {De Feyter}, Henk and Kyle Hurth and Shaobo Li and Joseph Wiemels and Brooke Nakamura and Ling Shao and Camelia Danilov and Thomas Chen and Josh Neman",
note = "Funding Information: We acknowledge all patients with pediatric brain tumors, including Anthony Jose De La Torre, and patient advocates, including Carolina Valls, who have helped us better understand this devastating disease. This project is supported by Keck School of Medicine of USC {\textquoteright}s Dean Pilot Project Grant, American Brain Tumor Association Discovery Grant DG1600003 , and NIH P30 DK0485 s 22 . Funding Information: We acknowledge all patients with pediatric brain tumors, including Anthony Jose De La Torre, and patient advocates, including Carolina Valls, who have helped us better understand this devastating disease. This project is supported by Keck School of Medicine of USC's Dean Pilot Project Grant, American Brain Tumor Association Discovery Grant DG1600003, and NIH P30 DK0485s22. Conceptualization, V.M. and J.N.; methodology, V.M. and J.N.; software, J.R. A.B. K. Smith, and P.N.; validation, V.M. H.Z. K. Shen, A.B. and K. Smith; formal analysis, V.M. J.R. S.L. and J.W.; investigation, V.M. K.D. V.S. H.Z. M.L. D.D. J.R. D.I. H.D.F. K.H. S.L. B.N. and L.S.; resources, J.N. L.S. K. Shen, A.B. T.C. P.N. and C.D.; writing – original draft, V.M. J.N. H.Z. J.R. and S.L.; writing – review & editing, V.M. and J.N.; visualization, V.M. and J.N.; supervision, J.N.; funding acquisition, J.N. T.C. is CEO of Neonc Technologies. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = jun,
day = "29",
doi = "10.1016/j.celrep.2021.109302",
language = "English (US)",
volume = "35",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "13",
}