2. Academic Validation
  3. Medulloblastoma uses GABA transaminase to survive in the cerebrospinal fluid microenvironment and promote leptomeningeal dissemination

Medulloblastoma uses GABA transaminase to survive in the cerebrospinal fluid microenvironment and promote leptomeningeal dissemination

  • Cell Rep. 2021 Jun 29;35(13):109302. doi: 10.1016/j.celrep.2021.109302.
Vahan Martirosian 1,  Krutika Deshpande 1,  Hao Zhou 2,  Keyue Shen 3,  Kyle Smith 4,  Paul Northcott 4,  Michelle Lin 5,  Vazgen Stepanosyan 5,  Diganta Das 5,  Jan Remsik 6,  Danielle Isakov 6,  Adrienne Boire 6,  Henk De Feyter 7,  Kyle Hurth 8,  Shaobo Li 9,  Joseph Wiemels 10,  Brooke Nakamura 11,  Ling Shao 12,  Camelia Danilov 5,  Thomas Chen 1,  Josh Neman 13
Affiliations

Affiliations

  • 1 Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; USC Brain Tumor Center, University of Southern California, Los Angeles, CA 90089, USA.
  • 2 Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA.
  • 3 Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
  • 4 Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 5 Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
  • 6 Human Oncology and Pathogenesis Program, Department of Neuro-Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 7 Magnetic Resonance Research Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT 06510, USA.
  • 8 Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; USC Brain Tumor Center, University of Southern California, Los Angeles, CA 90089, USA.
  • 9 Center for Genetic Epidemiology, Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
  • 10 Center for Genetic Epidemiology, Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
  • 11 Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
  • 12 Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
  • 13 Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA; USC Brain Tumor Center, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: yebrahim@usc.edu.
PMID: 34192534 DOI: 10.1016/j.celrep.2021.109302
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.

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