Cell Reports (Jun 2021)
Medulloblastoma uses GABA transaminase to survive in the cerebrospinal fluid microenvironment and promote leptomeningeal dissemination
- Vahan Martirosian,
- Krutika Deshpande,
- Hao Zhou,
- Keyue Shen,
- Kyle Smith,
- Paul Northcott,
- Michelle Lin,
- Vazgen Stepanosyan,
- Diganta Das,
- Jan Remsik,
- Danielle Isakov,
- Adrienne Boire,
- Henk De Feyter,
- Kyle Hurth,
- Shaobo Li,
- Joseph Wiemels,
- Brooke Nakamura,
- Ling Shao,
- Camelia Danilov,
- Thomas Chen,
- Josh Neman
Affiliations
- Vahan Martirosian
- 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
- Krutika Deshpande
- 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
- Hao Zhou
- Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA
- Keyue Shen
- 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
- Kyle Smith
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Paul Northcott
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Michelle Lin
- Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
- Vazgen Stepanosyan
- Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
- Diganta Das
- Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
- Jan Remsik
- Human Oncology and Pathogenesis Program, Department of Neuro-Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Danielle Isakov
- Human Oncology and Pathogenesis Program, Department of Neuro-Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Adrienne Boire
- Human Oncology and Pathogenesis Program, Department of Neuro-Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Henk De Feyter
- Magnetic Resonance Research Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT 06510, USA
- Kyle Hurth
- 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
- Shaobo Li
- Center for Genetic Epidemiology, Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
- Joseph Wiemels
- 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
- Brooke Nakamura
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
- Ling Shao
- 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
- Camelia Danilov
- Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
- Thomas Chen
- 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
- Josh Neman
- 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; Corresponding author
- Journal volume & issue
-
Vol. 35,
no. 13
p. 109302
Abstract
Summary: 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.
