Title
A driver role for GABA metabolism in controlling stem and proliferative cell state through GHB production in glioma
Author
El-Habr, Elias A. (UPMC-Sorbonne Universités & CNRS)
Dubois, Luiz G. (Secretaria de Estado de Saúde do Rio de Janeiro/RJ; UPMC-Sorbonne Universités & CNRS)
Burel-Vandenbos, Fanny (Université de Nice-Sophia Antipolis)
Bogeas, Alexandra (UPMC-Sorbonne Universités & CNRS)
Lipecka, Joanna (Paris Descartes University; UPMC-Sorbonne Universités & CNRS)
Turchi, Laurent (Inserm U1091)
Lejeune, François Xavier (UPMC-Sorbonne Universités & CNRS)
Coehlo, Paulo Lucas Cerqueira (UPMC-Sorbonne Universités & CNRS)
Yamaki, Tomohiro (ENS-PSL Research University & CNRS)
Wittmann, Bryan M. (Metabolon, Inc.)
Fareh, M. (TU Delft BN/Chirlmin Joo Lab; Université de Nice-Sophia Antipolis; Kavli institute of nanoscience Delft)
Mahfoudhi, Emna (Institut Gustave Roussy)
Janin, Maxime (Paris Descartes University)
Narayanan, Ashwin (UPMC-Sorbonne Universités & CNRS)
Morvan-Dubois, Ghislaine (UPMC-Sorbonne Universités & CNRS)
Schmitt, Charlotte (UPMC-Sorbonne Universités & CNRS)
Verreault, Maité (UPMC-Sorbonne Universités & CNRS)
Oliver, Lisa (Université de Nantes)
Sharif, Ariane (School of Medicine)
Pallud, Johan (Paris Descartes University)
Devaux, Bertrand (Paris Descartes University; UPMC-Sorbonne Universités & CNRS)
Puget, Stéphanie (Necker-Enfants Malades Hospital)
Korkolopoulou, Penelope (National and Capodistrian University of Athens)
Varlet, Pascale (Paris Descartes University)
Ottolenghi, Chris (Paris Descartes University)
Plo, Isabelle (Institut Gustave Roussy)
Moura-Neto, Vivaldo (Secretaria de Estado de Saúde do Rio de Janeiro/RJ)
Virolle, Thierry (Université de Nice-Sophia Antipolis)
Chneiweiss, Hervé (UPMC-Sorbonne Universités & CNRS)
Junier, Marie Pierre (UPMC-Sorbonne Universités & CNRS)
Date
2017
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.
Subject
5-hmC
ALDH5A1
Brain cancer
Cancer stem cell
DIPG
GABA
Valproate
To reference this document use:
http://resolver.tudelft.nl/uuid:65907cbe-8f7d-42b7-9ca1-4480c3c6ecd4
DOI
https://doi.org/10.1007/s00401-016-1659-5
ISSN
0001-6322
Source
Acta Neuropathologica, 133 (4), 645-660
Part of collection
Institutional Repository
Document type
journal article
Rights
© 2017 Elias A. El-Habr, Luiz G. Dubois, Fanny Burel-Vandenbos, Alexandra Bogeas, Joanna Lipecka, Laurent Turchi, François Xavier Lejeune, Paulo Lucas Cerqueira Coehlo, Tomohiro Yamaki, Bryan M. Wittmann, M. Fareh, Emna Mahfoudhi, Maxime Janin, Ashwin Narayanan, Ghislaine Morvan-Dubois, Charlotte Schmitt, Maité Verreault, Lisa Oliver, Ariane Sharif, Johan Pallud, Bertrand Devaux, Stéphanie Puget, Penelope Korkolopoulou, Pascale Varlet, Chris Ottolenghi, Isabelle Plo, Vivaldo Moura-Neto, Thierry Virolle, Hervé Chneiweiss, Marie Pierre Junier