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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1659-5) contains supplementary material, which is available to authorized users.

Capture at the single cell level of metabolic modules distinguishing aggressive and indolent glioblastoma cells

“…Flavahan and colleagues demonstrated that up-regulation of the high-affinity glucose transporter GLUT3 promotes acquisition by GBM cells of tumorigenic properties [23]. Conversely, we found that decreased activity of the mitochondrial enzyme SSADH triggers GBM cell conversion into a less aggressive functioning state, by coupling enhanced levels of the GABA byproduct GHB to altered epigenetic regulations [18]. These metabolic variations have been found to take place within the patient tumors, and to be coherently linked with relevant phenotypic markers [18], or patients' clinical course [12,23].…”

“…Conversely, we found that decreased activity of the mitochondrial enzyme SSADH triggers GBM cell conversion into a less aggressive functioning state, by coupling enhanced levels of the GABA byproduct GHB to altered epigenetic regulations [18]. These metabolic variations have been found to take place within the patient tumors, and to be coherently linked with relevant phenotypic markers [18], or patients' clinical course [12,23]. Metabolism is also emerging as a player in GBM therapeutic resistance, as exemplified by escape from the anti-angiogenic Bevacizumab treatment.…”

“…Patient-derived cells (PDC) 6240**, R633 and 5706** were obtained from neurosurgical biopsy samples of distinct primary GBM, characterized and cultured as described [18,57]. (Table S1) was achieved as described [4,18].…”

“…Patient-derived cells (PDC) 6240**, R633 and 5706** were obtained from neurosurgical biopsy samples of distinct primary GBM, characterized and cultured as described [18,57]. (Table S1) was achieved as described [4,18]. Viable cell counting, gene expression analysis, intracranial xenografts, and bioluminescence imaging (Table S1) were performed as described [4,18]).…”

A pan‐cancer atlas of cancer hallmark‐associated candidate driver lncRNAs

“…For example, in the hallmark ‘Evading Immune Detection’, we found that GO term ‘regulation of defense response to virus’ was only affected by mutually exclusive modules in HNSC, which is consistent with the prevalence and the roles of human papillomavirus in directly inhibiting innate immune system for this cancer type (Bodily and Laimins, ; Maxwell et al ., ). Similarly, GO term ‘neurotransmitter secretion’ in the hallmark ‘Self Sufficiency in Growth Signals’ was unique to GBM and LGG, in which neurotransmitters such as dopamine and GABA , have proved to govern cell proliferation (Dolma et al ., ; El‐Habr et al ., ).…”