Medulloblastoma uses GABA transaminase to survive in the cerebrospinal fluid microenvironment and promote leptomeningeal dissemination.
4-Aminobutyrate Transaminase
/ metabolism
Acetylation
Animals
Cell Differentiation
Cell Line, Tumor
Cell Proliferation
Cell Survival
Cerebellar Neoplasms
/ cerebrospinal fluid
Female
Histone Deacetylases
/ metabolism
Histones
/ metabolism
Lysine
/ metabolism
Medulloblastoma
/ cerebrospinal fluid
Meningeal Neoplasms
/ secondary
Meninges
/ pathology
Mice, Nude
Mitochondria
/ metabolism
Neurons
/ metabolism
Oxidative Phosphorylation
Phenotype
Rats
Tumor Microenvironment
gamma-Aminobutyric Acid
/ metabolism
ABAT
GABA shunt
cerebrospinal fluid
leptomeningeal disease
medulloblastoma
oxidative phosphorylation
tumor dormancy
tumor microenvironment
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
29 06 2021
29 06 2021
Historique:
received:
08
07
2020
revised:
02
10
2020
accepted:
03
06
2021
entrez:
30
6
2021
pubmed:
1
7
2021
medline:
11
2
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34192534
pii: S2211-1247(21)00678-1
doi: 10.1016/j.celrep.2021.109302
pmc: PMC8848833
mid: NIHMS1774599
pii:
doi:
Substances chimiques
Histones
0
gamma-Aminobutyric Acid
56-12-2
4-Aminobutyrate Transaminase
EC 2.6.1.19
Histone Deacetylases
EC 3.5.1.98
histone deacetylase 3
EC 3.5.1.98
Lysine
K3Z4F929H6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
109302Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014089
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK048522
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests T.C. is CEO of Neonc Technologies.
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