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Acta Neuropathol. 2017 Apr;133(4):645-660. doi: 10.1007/s00401-016-1659-5. Epub 2016 Dec 28.

A driver role for GABA metabolism in controlling stem and proliferative cell state through GHB production in glioma.

Author information

1
CNRS UMR8246, Inserm U1130, UPMC, Neuroscience Paris Seine-IBPS, Sorbonne Universities, 75005, Paris, France.
2
Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria de Estado de Saúde do Rio de Janeiro/RJ, Rio De Janeiro, CEP 20231-092, Brazil.
3
Université de Nice-Sophia Antipolis, Institut de Biologie Valrose, CNRS UMR7277, Inserm U1091, Nice, France.
4
Laboratoire Central d'Anatomie Pathologique, Hôpital Pasteur, University of Nice-Sophia-Antipolis, Nice, France.
5
The CPN Proteomics Facility-3P5, Inserm, U894, Paris Descartes University, 75014, Paris, France.
6
CNRS UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, UPMC, Sorbonne Universities, Paris, France.
7
Metabolon, Inc., Durham, NC, 27713, USA.
8
Department of Bionanoscience, Kavli Institute of Nanoscience, Delft University of Technology, Lorentzweg 1, 2628 CJ, Delft, The Netherlands.
9
Inserm U1009, Institut Gustave Roussy, 94800, Villejuif, France.
10
Reference Center of Inherited Metabolic Diseases, University Paris Descartes, Hospital Necker Enfants Malades, APHP, Paris, France.
11
Department of Biochemistry, University Paris Descartes, Hospital Necker Enfants Malades, 75015, Paris, France.
12
Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, 75013, Paris, France.
13
Team 9 CRCNA, UMR 892 Inserm, 6299 CNRS, Université de Nantes, 44035, Nantes Cedex 07, France.
14
Inserm, Jean-Pierre Aubert Research Center, Development and Plasticity of the Neuroendocrine Brain, Unit 1172, France, UDSL, School of Medicine, Place de Verdun, 59045, Lille Cedex, France.
15
Department of Neurosurgery, Sainte-Anne Hospital, Paris Descartes University, 75014, Paris, France.
16
Department of Neurosurgery, Necker-Enfants Malades Hospital, 75015, Paris, France.
17
Department of Pathology, National and Capodistrian University of Athens, Athens, Greece.
18
Department of Neuropathology, Sainte-Anne Hospital, Paris Descartes University, Paris, France.
19
CNRS UMR8246, Inserm U1130, UPMC, Neuroscience Paris Seine-IBPS, Sorbonne Universities, 75005, Paris, France. herve.chneiweiss@inserm.fr.
20
CNRS UMR8246, Inserm U1130, UPMC, Neuroscience Paris Seine-IBPS, Sorbonne Universities, 75005, Paris, France. marie-pierre.junier@inserm.fr.

Abstract

Cell populations with differing proliferative, stem-like and tumorigenic states co-exist in most tumors and especially malignant gliomas. Whether metabolic variations can drive this heterogeneity by controlling dynamic changes in cell states is unknown. Metabolite profiling of human adult glioblastoma stem-like cells upon loss of their tumorigenicity revealed a switch in the catabolism of the GABA neurotransmitter toward enhanced production and secretion of its by-product GHB (4-hydroxybutyrate). This switch was driven by succinic semialdehyde dehydrogenase (SSADH) downregulation. Enhancing GHB levels via SSADH downregulation or GHB supplementation triggered cell conversion into a less aggressive phenotypic state. GHB affected adult glioblastoma cells with varying molecular profiles, along with cells from pediatric pontine gliomas. In all cell types, GHB acted by inhibiting α-ketoglutarate-dependent Ten-eleven Translocations (TET) activity, resulting in decreased levels of the 5-hydroxymethylcytosine epigenetic mark. In patients, low SSADH expression was correlated with high GHB/α-ketoglutarate ratios, and distinguished weakly proliferative/differentiated glioblastoma territories from proliferative/non-differentiated territories. Our findings support an active participation of metabolic variations in the genesis of tumor heterogeneity.

KEYWORDS:

5-hmC; ALDH5A1; Brain cancer; Cancer stem cell; DIPG; GABA; Valproate

PMID:
28032215
PMCID:
PMC5348560
DOI:
10.1007/s00401-016-1659-5
[Indexed for MEDLINE]
Free PMC Article

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