Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo
Open accessAbstract
Dysregulated metabolism is a hallmark of cancer cell lines, but little is known about the fate of glucose and other nutrients in tumors growing in their native microenvironment. To study tumor metabolism in vivo, we used an orthotopic mouse model of primary human glioblastoma (GBM). We infused (13)C-labeled nutrients into mice bearing three independent GBM lines, each with a distinct set of mutations. All three lines displayed glycolysis, as expected for aggressive tumors. They also displayed unexpected metabolic complexity, oxidizing glucose via pyruvate dehydrogenase and the citric acid cycle, and using glucose to supply anaplerosis and other biosynthetic activities. Comparing the tumors to surrounding brain revealed obvious metabolic differences, notably the accumulation of a large glutamine pool within the tumors. Many of these same activities were conserved in cells cultured ex vivo from the tumors. Thus GBM cells utilize mitochondrial glucose oxidation during aggressive tumor growth in vivo.
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Evidence for the necessity of glutamine for cancer progression is conflicted: some studies report tumours can grow well without glutamine, while others show cancers are glutamine-addicted.
“The evidence for the necessity of glutamine for cancer progression is conflicted: some studies have reported that tumours can grow well without glutamine [66,67], while others showed that cancers are glutamine-addicted [68,69,70].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [66]
The Results (‘Glutamine independence of cells derived from orthotopic GBMs’; page unavailable) show that tumor-derived neurospheres survived and grew without extracellular glutamine, but describe their growth as ‘at least a low rate,’ not growing well. The Discussion (page unavailable) also reports that the tumors synthesized and accumulated glutamine, so the finding is independence from an external supply, not growth without glutamine itself. The citation is attached to the glutamine-independent side of the citing sentence, not the glutamine-addicted side. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCancer tissue-of-origin has served as a successful way to select patients for chemotherapies targeting metabolism for decades, and environment can influence the efficacy of drugs targeting DHODH, mitochondrial complex I, and glutaminase.
“Cancer tissue-of-origin has served as a successful way to select patients for chemotherapies targeting metabolism for decades, and environment can also influence the efficacy of drugs targeting DHODH, mitochondrial complex I, and glutaminase (Davidson et al., 2016; Gui et al., 2016; Marin-Valencia et al., 2012; Sellers et al., 2015; Sykes et al., 2016; Tardito et al., 2015).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Marin-Valencia et al., 2012
Glutamine tracing studies have demonstrated that in some tumor tissues glutamine contributes minimally to TCA cycle intermediates, and those cancers can be resistant to glutaminase inhibition.
“Glutamine tracing studies have demonstrated that in some tumor tissues, glutamine contributes minimally to TCA cycle intermediates, and those cancers can be resistant to glutaminase inhibition (Davidson et al., 2016; Hensley et al., 2016; Marin-Valencia et al., 2012; Sellers et al., 2015; Tardito et al., 2015).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Marin-Valencia et al., 2012
A prior in vivo study using 13C-labeled glucose and glutamine tracers showed patient-derived xenografts from primary GBMs consume glutamine but do not readily convert it to glutamate; instead they oxidize glucose to make glutamate.
“A prior in vivo study using 13C-labeled glucose and glutamine tracers showed that patient-derived xenografts made from primary GBMs, ~95% of which are IDH wild-type, consume glutamine, but do not readily convert it to glutamate (Marin-Valencia et al., 2012).”
From Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma (2018) · cites this paper as Marin-Valencia et al., 2012
Isotope tracing studies in lung and glioblastoma tumors suggest that glutamine is a relatively minor source of TCA cycle carbon in some cancer cells growing in vivo.
“However, isotope tracing studies in both lung and glioblastoma tumors suggest that glutamine is a relatively minor source of TCA cycle carbon in some cancer cells growing in vivo, indicating that environmental context can drive fuel preferences (193, 194).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [194]
Human glioblastoma samples implanted into immunocompromised mouse brains accumulate glutamine relative to normal brain tissue.
“In addition, human glioblastoma samples implanted directly into the brains of immunocompromised mice were found to accumulate glutamine relative to the normal brain tissue (Marin-Valencia et al., 2012);”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Marin-Valencia et al., 2012
Tracing glucose-derived carbons in human patients and mouse models of glioblastoma and NSCLC reveals that in these contexts the principal source for TCA cycle intermediates is glucose, not glutamine.
“In fact, tracing the fate of glucose-derived carbons in human patients and in mouse models of glioblastoma and non-small cell lung carcinoma (NSCLC) reveals that at least in these tumorigenic contexts, the principal source for the TCA cycle intermediates is not glutamine, but glucose (Maher et al., 2012; Marin-Valencia et al., 2012; Sellers et al., 2015).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Marin-Valencia et al., 2012
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- Authors
- Marin-Valencia, I., Yang, C., Mashimo, T., Cho, S., Baek, H., Yang, X.-L., Rajagopalan, K. N., Maddie, M., Vemireddy, V., Zhao, Z., Cai, L., Good, L., Tu, B. P., Hatanpaa, K. J., Mickey, B. E., Matés, J. M., Pascual, J. M., Maher, E. A., Malloy, C. R., DeBerardinis, R. J., & Bachoo, R. M.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Universidad de Málaga (ES)
- VA North Texas Health Care System (US)
- Corresponding author
- DeBerardinis, Ralph J.
- Bachoo, Robert M.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 15
- Issue
- 6
- Pages
- 827-837
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3372870
- OpenAlex
- W2151980465
- Cited by
- 529
- References
- 40
- Citations by year
- 2026: 14 · 2025: 28 · 2024: 12 · 2023: 34 · 2022: 31 · 2021: 57 · 2020: 62 · 2019: 41 · 2018: 38 · 2017: 54 · 2016: 44 · 2015: 42 · 2014: 38 · 2013: 23 · 2012: 9
- FWCI
- 11.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA157996, R01CA154843, R01CA157996)
- National Institute of General Medical Sciences (R01GM094314)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK072565, K08DK072565)
- National Institute of Neurological Disorders and Stroke (R01NS065195, RC1NS0760675)
- National Center for Research Resources (P41RR002584, RR‐02584)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- glioblastoma, cancer metabolism, pyruvate dehydrogenase, TCA cycle, anaplerosis, glutamine accumulation, glycolysis, orthotopic mouse model, tumor microenvironment
- MeSH terms
- Animals, Brain Neoplasms, Glioblastoma, Gluconeogenesis, Glucose, Glutaminase, Glutamine, Glutamate-Ammonia Ligase, Glycolysis, Humans, Mitochondria, Neoplasm Transplantation, Oxidation-Reduction, Phenotype, Pyruvate Carboxylase, Tumor Cells, Cultured, Mice, SCID, Mice, Inbred NOD, Neostriatum, Glutamic Acid, Statistics, Nonparametric, Mice
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