TY - JOUR
T1 - A driver role for GABA metabolism in controlling stem and proliferative cell state through GHB production in glioma
AU - El-Habr, Elias A.
AU - Dubois, Luiz G.
AU - Burel-Vandenbos, Fanny
AU - Bogeas, Alexandra
AU - Lipecka, Joanna
AU - Turchi, Laurent
AU - Lejeune, François Xavier
AU - Coehlo, Paulo Lucas Cerqueira
AU - Yamaki, Tomohiro
AU - Wittmann, Bryan M.
AU - Fareh, Mohamed
AU - Mahfoudhi, Emna
AU - Janin, Maxime
AU - Narayanan, Ashwin
AU - Morvan-Dubois, Ghislaine
AU - Schmitt, Charlotte
AU - Verreault, Maité
AU - Oliver, Lisa
AU - Sharif, Ariane
AU - Pallud, Johan
AU - Devaux, Bertrand
AU - Puget, Stéphanie
AU - Korkolopoulou, Penelope
AU - Varlet, Pascale
AU - Ottolenghi, Chris
AU - Plo, Isabelle
AU - Moura-Neto, Vivaldo
AU - Virolle, Thierry
AU - Chneiweiss, Hervé
AU - Junier, Marie Pierre
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - 5-hmC
KW - ALDH5A1
KW - Brain cancer
KW - Cancer stem cell
KW - DIPG
KW - GABA
KW - Valproate
UR - http://resolver.tudelft.nl/uuid:65907cbe-8f7d-42b7-9ca1-4480c3c6ecd4
UR - http://www.scopus.com/inward/record.url?scp=85007453500&partnerID=8YFLogxK
U2 - 10.1007/s00401-016-1659-5
DO - 10.1007/s00401-016-1659-5
M3 - Article
C2 - 28032215
SN - 0001-6322
VL - 133
SP - 645
EP - 660
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 4
ER -
