title: A driver role for GABA metabolism in controlling stem and proliferative cell state through GHB production in glioma.
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.
authors.affiliation: CNRS UMR8246, Inserm U1130, UPMC, Neuroscience Paris Seine-IBPS, Sorbonne Universities, 75005, Paris, France.
authors.forename: Elias A
authors.initials: EA
authors.lastname: El-Habr
authors.affiliation: CNRS UMR8246, Inserm U1130, UPMC, Neuroscience Paris Seine-IBPS, Sorbonne Universities, 75005, Paris, France.|Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria de Estado de Saúde do Rio de Janeiro/RJ, Rio De Janeiro, CEP 20231-092, Brazil.
authors.forename: Luiz G
authors.initials: LG
authors.lastname: Dubois
authors.affiliation: Université de Nice-Sophia Antipolis, Institut de Biologie Valrose, CNRS UMR7277, Inserm U1091, Nice, France.|Laboratoire Central d'Anatomie Pathologique, Hôpital Pasteur, University of Nice-Sophia-Antipolis, Nice, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Burel-Vandenbos
authors.affiliation: CNRS UMR8246, Inserm U1130, UPMC, Neuroscience Paris Seine-IBPS, Sorbonne Universities, 75005, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Bogeas
authors.affiliation: CNRS UMR8246, Inserm U1130, UPMC, Neuroscience Paris Seine-IBPS, Sorbonne Universities, 75005, Paris, France.|The CPN Proteomics Facility-3P5, Inserm, U894, Paris Descartes University, 75014, Paris, France.
authors.forename: Joanna
authors.initials: J
authors.lastname: Lipecka
authors.affiliation: Université de Nice-Sophia Antipolis, Institut de Biologie Valrose, CNRS UMR7277, Inserm U1091, Nice, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Turchi
authors.affiliation: CNRS UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, UPMC, Sorbonne Universities, Paris, France.
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Lejeune
authors.affiliation: CNRS UMR8246, Inserm U1130, UPMC, Neuroscience Paris Seine-IBPS, Sorbonne Universities, 75005, Paris, France.
authors.forename: Paulo Lucas Cerqueira
authors.initials: PL
authors.lastname: Coehlo
authors.affiliation: CNRS UMR8246, Inserm U1130, UPMC, Neuroscience Paris Seine-IBPS, Sorbonne Universities, 75005, Paris, France.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yamaki
authors.affiliation: Metabolon, Inc., Durham, NC, 27713, USA.
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Wittmann
authors.affiliation: Université de Nice-Sophia Antipolis, Institut de Biologie Valrose, CNRS UMR7277, Inserm U1091, Nice, France.|Department of Bionanoscience, Kavli Institute of Nanoscience, Delft University of Technology, Lorentzweg 1, 2628 CJ, Delft, The Netherlands.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Fareh
authors.affiliation: Inserm U1009, Institut Gustave Roussy, 94800, Villejuif, France.
authors.forename: Emna
authors.initials: E
authors.lastname: Mahfoudhi
authors.affiliation: Reference Center of Inherited Metabolic Diseases, University Paris Descartes, Hospital Necker Enfants Malades, APHP, Paris, France.|Department of Biochemistry, University Paris Descartes, Hospital Necker Enfants Malades, 75015, Paris, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Janin
authors.affiliation: CNRS UMR8246, Inserm U1130, UPMC, Neuroscience Paris Seine-IBPS, Sorbonne Universities, 75005, Paris, France.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Narayanan
authors.affiliation: CNRS UMR8246, Inserm U1130, UPMC, Neuroscience Paris Seine-IBPS, Sorbonne Universities, 75005, Paris, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Morvan-Dubois
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, 75013, Paris, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Schmitt
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, 75013, Paris, France.
authors.forename: Maité
authors.initials: M
authors.lastname: Verreault
authors.affiliation: Team 9 CRCNA, UMR 892 Inserm, 6299 CNRS, Université de Nantes, 44035, Nantes Cedex 07, France.
authors.forename: Lisa
authors.initials: L
authors.lastname: Oliver
authors.affiliation: 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.
authors.forename: Ariane
authors.initials: A
authors.lastname: Sharif
authors.affiliation: Department of Neurosurgery, Sainte-Anne Hospital, Paris Descartes University, 75014, Paris, France.
authors.forename: Johan
authors.initials: J
authors.lastname: Pallud
authors.affiliation: CNRS UMR8246, Inserm U1130, UPMC, Neuroscience Paris Seine-IBPS, Sorbonne Universities, 75005, Paris, France.|Department of Neurosurgery, Sainte-Anne Hospital, Paris Descartes University, 75014, Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Devaux
authors.affiliation: Department of Neurosurgery, Necker-Enfants Malades Hospital, 75015, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Puget
authors.affiliation: Department of Pathology, National and Capodistrian University of Athens, Athens, Greece.
authors.forename: Penelope
authors.initials: P
authors.lastname: Korkolopoulou
authors.affiliation: Department of Neuropathology, Sainte-Anne Hospital, Paris Descartes University, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Varlet
authors.affiliation: Reference Center of Inherited Metabolic Diseases, University Paris Descartes, Hospital Necker Enfants Malades, APHP, Paris, France.|Department of Biochemistry, University Paris Descartes, Hospital Necker Enfants Malades, 75015, Paris, France.
authors.forename: Chris
authors.initials: C
authors.lastname: Ottolenghi
authors.affiliation: Inserm U1009, Institut Gustave Roussy, 94800, Villejuif, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Plo
authors.affiliation: Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria de Estado de Saúde do Rio de Janeiro/RJ, Rio De Janeiro, CEP 20231-092, Brazil.
authors.forename: Vivaldo
authors.initials: V
authors.lastname: Moura-Neto
authors.affiliation: Université de Nice-Sophia Antipolis, Institut de Biologie Valrose, CNRS UMR7277, Inserm U1091, Nice, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Virolle
authors.affiliation: CNRS UMR8246, Inserm U1130, UPMC, Neuroscience Paris Seine-IBPS, Sorbonne Universities, 75005, Paris, France. herve.chneiweiss@inserm.fr.
authors.forename: Hervé
authors.initials: H
authors.lastname: Chneiweiss
authors.affiliation: CNRS UMR8246, Inserm U1130, UPMC, Neuroscience Paris Seine-IBPS, Sorbonne Universities, 75005, Paris, France. marie-pierre.junier@inserm.fr.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Junier
mesh_terms: D000368:Aged; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005910:Glioma / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D006801:Humans; D006885:Hydroxybutyrates / Q000378:metabolism*; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D050644:Succinate-Semialdehyde Dehydrogenase / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D006885:Hydroxybutyrates; C111420:4-hydroxybutyric acid; D005680:gamma-Aminobutyric Acid; C493643:ALDH5A1 protein, human; D050644:Succinate-Semialdehyde Dehydrogenase
keywords: 5-hmC; ALDH5A1; Brain cancer; Cancer stem cell; DIPG; GABA; Valproate