Glutamine uptake and utilization of human mesenchymal glioblastoma in orthotopic mouse model

Oizel, Kristell; Yang, Chendong; Renoult, Ophélie; Gautier, Fabien; Quyen, N.; Joalland, Noémie; Gao, Xiaofei; Ko, Bookyung; Vallette, François M.; Ge, Woo-Ping; Pâris, François; DeBerardinis, Ralph J.; Pecqueur, Claire

doi:10.1186/s40170-020-00215-8

Cited by 25 publications

(21 citation statements)

References 35 publications

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“…Glutamine catabolism independence has also been reported in other in vivo tumor models [39]. In the context of glioblastoma, some studies have maintained that pyruvate-derived carbons dominate those coming from glutamine in the TCA cycle [39,40], while another recent study showed that the origin of the glioblastoma cells influences their preference of anaplerotic substrate [45]. Overall, dependence on glutamine oxidation appears to be heterogenous, and dictated by underlying genetics [43,46], tissue origin [46], and tumor microenvironment [44,47], and glutamine auxotrophy may not be a universal characteristic of cancer cells in vivo.…”

Section: Discussionmentioning

confidence: 80%

Impaired anaplerosis is a major contributor to glycolysis inhibitor toxicity in glioma

et al. 2021

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Background Reprogramming of metabolic pathways is crucial to satisfy the bioenergetic and biosynthetic demands and maintain the redox status of rapidly proliferating cancer cells. In tumors, the tricarboxylic acid (TCA) cycle generates biosynthetic intermediates and must be replenished (anaplerosis), mainly from pyruvate and glutamine. We recently described a novel enolase inhibitor, HEX, and its pro-drug POMHEX. Since glycolysis inhibition would deprive the cell of a key source of pyruvate, we hypothesized that enolase inhibitors might inhibit anaplerosis and synergize with other inhibitors of anaplerosis, such as the glutaminase inhibitor, CB-839. Methods We analyzed polar metabolites in sensitive (ENO1-deleted) and resistant (ENO1-WT) glioma cells treated with enolase and glutaminase inhibitors. We investigated whether sensitivity to enolase inhibitors could be attenuated by exogenous anaplerotic metabolites. We also determined the synergy between enolase inhibitors and the glutaminase inhibitor CB-839 in glioma cells in vitro and in vivo in both intracranial and subcutaneous tumor models. Results Metabolomic profiling of ENO1-deleted glioma cells treated with the enolase inhibitor revealed a profound decrease in the TCA cycle metabolites with the toxicity reversible upon exogenous supplementation of supraphysiological levels of anaplerotic substrates, including pyruvate. ENO1-deleted cells also exhibited selective sensitivity to the glutaminase inhibitor CB-839, in a manner rescuable by supplementation of anaplerotic substrates or plasma-like media PlasmaxTM. In vitro, the interaction of these two drugs yielded a strong synergistic interaction but the antineoplastic effects of CB-839 as a single agent in ENO1-deleted xenograft tumors in vivo were modest in both intracranial orthotopic tumors, where the limited efficacy could be attributed to the blood-brain barrier (BBB), and subcutaneous xenografts, where BBB penetration is not an issue. This contrasts with the enolase inhibitor HEX, which, despite its negative charge, achieved antineoplastic effects in both intracranial and subcutaneous tumors. Conclusion Together, these data suggest that at least for ENO1-deleted gliomas, tumors in vivo—unlike cells in culture—show limited dependence on glutaminolysis and instead primarily depend on glycolysis for anaplerosis. Our findings reinforce the previously reported metabolic idiosyncrasies of in vitro culture and suggest that cell culture media nutrient composition more faithful to the in vivo environment will more accurately predict in vivo efficacy of metabolism targeting drugs.

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Section: Discussionmentioning

confidence: 80%

Impaired anaplerosis is a major contributor to glycolysis inhibitor toxicity in glioma

et al. 2021

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“…Glutamine catabolism independence has also been reported in in vivo tumor models (38). In the context of glioblastoma, some studies have maintained that pyruvate-derived carbons dominate those coming from glutamine in the TCA cycle (38,39), while another recent study showed that the origin of the glioblastoma cells influences their preference of anaplerotic substrate (43). Overall, dependence on glutamine oxidation appears to be heterogenous, and dictated by underlying genetics (16,44), tissue origin (44), and tumor microenvironment (42,45) and glutamine auxotrophy may not be a universal characteristic of cancer cells in vivo.…”

Section: Discussionmentioning

confidence: 91%

Impaired Anaplerosis Is a Major Contributor to Glycolysis Inhibitor Toxicity in Glioma

Khadka

Arthur

Washington

et al. 2020

Preprint

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Reprogramming of metabolic pathways is crucial to satisfy the bioenergetic and biosynthetic demands and maintain the redox status of rapidly proliferating cancer cells. In tumors, the tricarboxylic acid (TCA) cycle generates biosynthetic intermediates by oxidation of anaplerotic substrates, such as glucose-derived pyruvate and glutamine20 derived glutamate. We have previously documented that a subset of tumors with 1p36 homozygous deletion exhibit co-deletion of ENO1, in turn becoming extremely dependent on its redundant isoform ENO2 and sensitive to an overall enzymatic deficiency of enolase. Metabolomic profiling of ENO1-deleted glioma cells treated with an enolase inhibitor revealed a profound decrease in TCA cycle metabolites, which correlated with cell-line specific sensitivity to enolase inhibition, highlighting the importance of glycolysis derived pyruvate for anaplerosis. Correspondingly, the toxicity of the enolase inhibitor was significantly attenuated by exogenous supplementation of supraphysiological levels of anaplerotic substrates including pyruvate. These findings led us to hypothesize that cancer cells with ENO1 homozygous deletions treated with an enolase inhibitor might show exceptional sensitivity to inhibition of glutaminolysis because of reduced anaplerotic flow from glycolysis. We found that ENO1-deleted cells indeed exhibited selective sensitivity to the glutaminase inhibitor CB-839, and this sensitivity was also attenuated by exogenous supplementation of anaplerotic substrates including pyruvate. Despite these promising in vitro results, the antineoplastic effects of CB-839 as a single agent in ENO1-deleted xenograft tumors in vivo were modest in both intracranial orthotopic tumors, where the limited efficacy could be attributed to the blood brain barrier (BBB), and subcutaneous xenografts, where BBB penetration is not an issue. This contrasts with the enolase inhibitor HEX, which, despite its negative charge, achieved antineoplastic effects in both intracranial and subcutaneous tumors. Together, these data suggest that at least for 1p36-deleted gliomas, tumors in vivo—unlike cells in culture—show limited dependence on glutaminolysis and instead primarily depend on glycolysis for anaplerosis. Our findings reinforce the previously reported metabolic idiosyncrasies of the in vitro and in vivo environments as the potential reasons for the differential efficacy of metabolism targeted therapies in in vitro and in vivo systems.

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“…Interestingly, the group of patient-derived GSCs that uptake high glutamine levels, transcriptomically classifies as the GBM mesenchymal subtype, while the glucose-dependent group does not ( Oizel et al, 2017 ). Not surprisingly, tumours generated by mesenchymal GSCs show increased glutamine uptake and conversion to glutamate when compared to non-mesenchymal GSCs ( Oizel et al, 2020 ). In the same study, it was shown that the non-mesenchymal GSCs (which belong to the proneural and classical subtypes) express high levels of GS ( Oizel et al, 2020 ).…”

Section: Glioblastomamentioning

confidence: 99%

“…Not surprisingly, tumours generated by mesenchymal GSCs show increased glutamine uptake and conversion to glutamate when compared to non-mesenchymal GSCs ( Oizel et al, 2020 ). In the same study, it was shown that the non-mesenchymal GSCs (which belong to the proneural and classical subtypes) express high levels of GS ( Oizel et al, 2020 ). These studies seem to contradict the work mentioned earlier by Tardito et al (2015) and Marin-Valencia et al (2012) , in which the authors described that the stem-like population does not depend on glutamine.…”

Section: Glioblastomamentioning

confidence: 99%

Glucose and Amino Acid Metabolic Dependencies Linked to Stemness and Metastasis in Different Aggressive Cancer Types

et al. 2021

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Malignant cells are commonly characterised by being capable of invading tissue, growing self-sufficiently and uncontrollably, being insensitive to apoptosis induction and controlling their environment, for example inducing angiogenesis. Amongst them, a subpopulation of cancer cells, called cancer stem cells (CSCs) shows sustained replicative potential, tumor-initiating properties and chemoresistance. These characteristics make CSCs responsible for therapy resistance, tumor relapse and growth in distant organs, causing metastatic dissemination. For these reasons, eliminating CSCs is necessary in order to achieve long-term survival of cancer patients. New insights in cancer metabolism have revealed that cellular metabolism in tumors is highly heterogeneous and that CSCs show specific metabolic traits supporting their unique functionality. Indeed, CSCs adapt differently to the deprivation of specific nutrients that represent potentially targetable vulnerabilities. This review focuses on three of the most aggressive tumor types: pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC) and glioblastoma (GBM). The aim is to prove whether CSCs from different tumour types share common metabolic requirements and responses to nutrient starvation, by outlining the diverse roles of glucose and amino acids within tumour cells and in the tumour microenvironment, as well as the consequences of their deprivation. Beyond their role in biosynthesis, they serve as energy sources and help maintain redox balance. In addition, glucose and amino acid derivatives contribute to immune responses linked to tumourigenesis and metastasis. Furthermore, potential metabolic liabilities are identified and discussed as targets for therapeutic intervention.

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Glutamine uptake and utilization of human mesenchymal glioblastoma in orthotopic mouse model

Cited by 25 publications

References 35 publications

Impaired anaplerosis is a major contributor to glycolysis inhibitor toxicity in glioma

Impaired anaplerosis is a major contributor to glycolysis inhibitor toxicity in glioma

Impaired Anaplerosis Is a Major Contributor to Glycolysis Inhibitor Toxicity in Glioma

Glucose and Amino Acid Metabolic Dependencies Linked to Stemness and Metastasis in Different Aggressive Cancer Types

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