In Vivo Imaging of Glutamine Metabolism to the Oncometabolite 2-Hydroxyglutarate in IDH1/2 Mutant Tumors
Open accessAbstract
The oncometabolite 2-hydroxyglutarate (2-HG) is a signature biomarker in various cancers, where it accumulates as a result of mutations in isocitrate dehydrogenase (IDH). The metabolic source of 2-HG, in a wide variety of cancers, dictates both its generation and also potential therapeutic strategies, but this remains difficult to access in vivo. Here, utilizing patient-derived chondrosarcoma cells harboring endogenous mutations in IDH1 and IDH2, we report that 2-HG can be rapidly generated from glutamine in vitro. Then, using hyperpolarized magnetic resonance imaging (HP-MRI), we demonstrate that in vivo HP [1-13 C] glutamine can be used to non-invasively measure glutamine-derived HP 2-HG production. This can be readily modulated utilizing a selective IDH1 inhibitor, opening the door to targeting glutamine-derived 2-HG therapeutically. Rapid rates of HP 2-HG generation in vivo further demonstrate that, in a context-dependent manner, glutamine can be a primary carbon source for 2-HG production in mutant IDH tumors.
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Depending on tissue of origin, cancer cells use various routes of glutamine metabolism; some require exogenous glutamine for malignant proliferation, whereas others do not and can synthesize it de novo.
“Furthermore, depending on the tissue of origin, cancer cells use various routes of glutamine metabolism. Some have been shown to require an exogenous glutamine supply for malignant proliferation [71,72], whereas others do not [73] and can synthesize it de novo [74].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [72]
The Results section reports that glutamine is the main source of 2-hydroxyglutarate in two IDH-mutant chondrosarcoma cell lines, and that glutamine depletion greatly reduces its accumulation in one line. This supports glutamine-dependent metabolism, but the passages do not establish that exogenous glutamine is required for malignant proliferation. The separate claims about cells that do not require exogenous glutamine and synthesize it de novo are attached to other citations. (LLM, conf=0.79)
Experimental — accuracy not yet measuredGeneration of R-2-HG from glutamine occurs rapidly in patient-derived chondrosarcoma cell lines harboring endogenous IDH mutations.
“Interestingly, the generation of R-2-HG from glutamine has been proven to occur rapidly in patient-derived chondrosarcoma cell lines harboring endogenous IDH mutations”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [121]
In IDH1/2 mutant cells, glutamine flux is directed toward R-2-HG generation, with kinetics similar to glutamate or α-KG formation via glutaminolysis.
“In this study, glutamine flux was directed toward the generation of R-2-HG in IDH1/2 mutant cells, and the kinetics of R-2-HG formation were proportionally of the same order of magnitude as those of glutamate or α-KG formation via glutaminolysis.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [121]
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Cites
A Simple Practice Guide for Dose Conversion between Animals and Human
Nair, A., & Jacob, S. (2016) · Journal of Basic and Clinical Pharmacy · doi:10.4103/0976-0105.177703 · Cited by 6,174 · see citing works
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
Dang, L., White, D. W., Gross, S., Bennett, B. D., Bittinger, M. A., Driggers, E. M., Fantin, V. R., Jang, H. G., Jin, S., Keenan, M. C., et al. (2009) · Nature · doi:10.1038/nature08617 · Cited by 4,154 · see citing works
Self-citationMetabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
Ward, P. S., & Thompson, C. B. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.014 · Cited by 3,233 · see citing works
Self-citationXu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H., Ito, S., Yang, C., Wang, P., Xiao, M.-T., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.014 · Cited by 2,875 · see citing works
DeBerardinis, R. J., Mancuso, A., Daikhin, E., Nissim, I., Yudkoff, M., Wehrli, S., & Thompson, C. B. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709747104 · Cited by 2,622 · see citing works
Self-citationWise, D. R., DeBerardinis, R. J., Mancuso, A., Sayed, N., Zhang, X.-Y., Pfeiffer, H. K., Nissim, I., Daikhin, E., Yudkoff, M., McMahon, S. B., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810199105 · Cited by 2,001 · see citing works
Self-citationIDH mutation impairs histone demethylation and results in a block to cell differentiation
Lu, C., Ward, P. S., Kapoor, G. S., Rohle, D., Turcan, S., Abdel-Wahab, O., Edwards, C. R., Khanin, R., Figueroa, M. E., Melnick, A., et al. (2012) · Nature · doi:10.1038/nature10860 · Cited by 1,985 · see citing works
Self-citationMetabolic Imaging of Patients with Prostate Cancer Using Hyperpolarized [1- 13 C]Pyruvate
Nelson, S. J., Kurhanewicz, J. V., Vigneron, D. B., Larson, P. E. Z., Harzstark, A. L., Ferrone, M., Criekinge, M. V., Chang, J. W., Bok, R., Park, I., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3006070 · Cited by 1,289 · see citing works
An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells
Rohle, D., Popovici-Muller, J., Palaskas, N., Turcan, S., Grommes, C., Campos, C., Tsoi, J., Clark, O., Oldrini, B., Komisopoulou, E., et al. (2013) · Science · doi:10.1126/science.1236062 · Cited by 1,153 · see citing works
Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate
Gallagher, F. A., Kettunen, M. I., Day, S. E., et al. (2008) · Nature · doi:10.1038/nature07017 · Cited by 851 · see citing works
2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas
Choi, C., Ganji, S. K., DeBerardinis, R. J., Hatanpaa, K. J., Rakheja, D., Kovacs, Z., Yang, X.-L., Mashimo, T., Raisanen, J. M., Marin-Valencia, I., et al. (2012) · Nature Medicine · doi:10.1038/nm.2682 · Cited by 839 · see citing works
Marcucci, G., Maharry, K. S., Wu, Y.-Z., Radmacher, M. D., Mrózek, K., Margeson, D., Holland, K. B., Whitman, S. P., Becker, H., Schwind, S., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.27.3730 · Cited by 763 · see citing works
Metabolic targets for cancer therapy
Galluzzi, L., Kepp, O., Heiden, M. G. V., & Kroemer, G. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4145 · Cited by 705 · see citing works
What a difference a hydroxyl makes: mutant IDH, (<i>R</i>)-2-hydroxyglutarate, and cancer
Losman, J.-A., & Kaelin, W. G. (2013) · Genes & Development · doi:10.1101/gad.217406.113 · Cited by 570 · see citing works
Inhibition of Glutaminase Preferentially Slows Growth of Glioma Cells with Mutant IDH1
Seltzer, M. J., Bennett, B. D., Joshi, A. D., Gao, P., Thomas, A. G., Ferraris, D. V., Tsukamoto, T., Rojas, C. J., Slusher, B. S., Rabinowitz, J. D., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-1666 · Cited by 513 · see citing works
Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome
Reitman, Z. J., Jin, G., Karoly, E. D., Spasojevic, I., Yang, J., Kinzler, K. W., He, Y., Bigner, D. D., Vogelstein, B., & Yan, H. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1019393108 · Cited by 449 · see citing works
Andronesi, O. C., Kim, G. S., Gerstner, E., Batchelor, T., Tzika, A. A., Fantin, V. R., Vander Heiden, M. G., & Sorensen, A. G. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3002693 · Cited by 438 · see citing works
Monoclonal antibody specific for IDH1 R132H mutation
Capper, D., Zentgraf, H., Balß, J., Hartmann, C. J., & von Deimling, A. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0595-z · Cited by 433 · see citing works
Extreme vulnerability of IDH1 mutant cancers to NAD+ depletion
Tateishi, K., Wakimoto, H., Iafrate, A. J., Tanaka, S., Loebel, F., Lelic, N., Wiederschain, D., Bedel, O., Deng, G., Zhang, B., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.11.006 · Cited by 433 · see citing works
Oncometabolites: linking altered metabolism with cancer
Yang, M. H., Soga, T., & Pollard, P. J. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67228 · Cited by 424 · see citing works
Metabolic reprogramming in cancer: Unraveling the role of glutamine in tumorigenesis
Daye, D., & Wellen, K. E. (2012) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2012.02.002 · Cited by 375 · see citing works
IDH mutations in glioma and acute myeloid leukemia
Dang, L., Jin, S., & Su, S.-S. M. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.07.002 · Cited by 368 · see citing works
MacKenzie, E. D., Selak, M. A., Tennant, D. A., Payne, L. J., Crosby, S., Frederiksen, C. M., Watson, D. G., & Gottlieb, E. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01927-06 · Cited by 359 · see citing works
Keshari, K. R., & Wilson, D. M. (2013) · Chemical Society Reviews · doi:10.1039/c3cs60124b · Cited by 357 · see citing works
Self-citationUse of PET for monitoring cancer therapy and for predicting outcome.
Weber, W. (2005) · PubMed · Cited by 338 · see citing works
Pope, W. B., Prins, R. M., Albert Thomas, M., Nagarajan, R., Yen, K. E., Bittinger, M. A., Salamon, N., Chou, A. P., Yong, W. H., Soto, H., et al. (2012) · Journal of Neuro-Oncology · doi:10.1007/s11060-011-0737-8 · Cited by 318 · see citing works
Glutamine-based PET imaging facilitates enhanced metabolic evaluation of gliomas in vivo
Venneti, S., Dunphy, M. P., Zhang, H., Pitter, K. L., Zanzonico, P., Campos, C., Carlin, S., Rocca, G. L., Lyashchenko, S. K., Plöessl, K., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa1009 · Cited by 314 · see citing works
Self-citationCancer-associated IDH mutations: biomarker and therapeutic opportunities
Yen, K. E., Bittinger, M. A., Su, S. M., & Fantin, V. R. (2010) · Oncogene · doi:10.1038/onc.2010.444 · Cited by 296 · see citing works
Grassian, A. R., Parker, S. J., Davidson, S. M., Divakaruni, A. S., Green, C. R., Zhang, X., Slocum, K. L., Pu, M., Lin, F., Vickers, C., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0772-t · Cited by 280 · see citing works
Turkalp, Z. T., Karamchandani, J., & Das, S. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2014.1205 · Cited by 222 · see citing works
IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives
de Botton, S., Mondesir, J., Willekens, C., & Touat, M. (2016) · Journal of Blood Medicine · doi:10.2147/jbm.s70716 · Cited by 220 · see citing works
IDH1 mutations in low-grade astrocytomas predict survival but not response to temozolomide
Dubbink, H. J., Taal, W., van Marion, R., Kros, J. M., van Heuvel, I., Bromberg, J. E. C., Zonnenberg, B. A., Zonnenberg, C. B. L., Postma, T. J., Gijtenbeek, J. M. M., et al. (2009) · Neurology · doi:10.1212/wnl.0b013e3181c34ace · Cited by 186 · see citing works
Ward, P. S., Lü, C., Cross, J. R., Abdel-Wahab, O. I., Levine, R. L., Schwartz, G. K., & Thompson, C. B. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.435495 · Cited by 181 · see citing works
Self-citationPET Imaging of Glutaminolysis in Tumors by 18 F-( 2S,4R )4-Fluoroglutamine
Lieberman, B. P., Plöessl, K., Wang, L., Qü, W., Zha, Z., Wise, D. R., Chodosh, L. A., Belka, G. K., Thompson, C. B., & Kung, H. F. (2011) · Journal of Nuclear Medicine · doi:10.2967/jnumed.111.093815 · Cited by 176 · see citing works
Self-citationDetection of oncogenic IDH1 mutations using magnetic resonance spectroscopy of 2-hydroxyglutarate
Andronesi, O. C., Rapalino, O., Gerstner, E. R., Chi, A. S., Batchelor, T. T., Cahill, D. P., Sorensen, A. G., & Rosen, B. R. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67229 · Cited by 174 · see citing works
Metabolic consequences of oncogenic IDH mutations
Parker, S. J., & Metallo, C. M. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.05.003 · Cited by 158 · see citing works
Oncometabolites: tailoring our genes
Nowicki, S., & Gottlieb, E. (2015) · FEBS Journal · doi:10.1111/febs.13295 · Cited by 145 · see citing works
Non-invasive in vivo assessment of IDH1 mutational status in glioma
Chaumeil, M. M., Larson, P. E. Z., Yoshihara, H. A. I., Danforth, O. M., Vigneron, D. B., Nelson, S. J., Pieper, R. O., Phillips, J. J., & Ronen, S. M. (2013) · Nature Communications · doi:10.1038/ncomms3429 · Cited by 139 · see citing works
Fathi, A. T., Sadrzadeh, H., Borger, D. R., Ballen, K. K., Amrein, P. C., Attar, E. C., Foster, J., Burke, M. E., Lopez, H. U., Matulis, C. R., et al. (2012) · Blood · doi:10.1182/blood-2012-06-438267 · Cited by 123 · see citing works
Quantitative metabolome analysis profiles activation of glutaminolysis in glioma with IDH1 mutation
Ohka, F., Ito, M., Ranjit, M., Senga, T., Motomura, A., Motomura, K., Saito, K., Kato, K., Kato, Y., Wakabayashi, T., et al. (2014) · Tumor Biology · doi:10.1007/s13277-014-1784-5 · Cited by 121 · see citing works
Glioma Cells with the IDH1 Mutation Modulate Metabolic Fractional Flux through Pyruvate Carboxylase
Izquierdo-García, J. L., Cai, L. M., Chaumeil, M. M., Eriksson, P., Robinson, A. E., Pieper, R. O., Phillips, J. J., & Ronen, S. M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0108289 · Cited by 73 · see citing works
In vivo and in vitro liver cancer metabolism observed with hyperpolarized [5-13C]glutamine
Cabella, C., Karlsson, M. G., Canapè, C., Catanzaro, G., Serra, S. C., Miragoli, L., Poggi, L., Uggeri, F., Venturi, L., Jensen, P. R., et al. (2013) · Journal of Magnetic Resonance · doi:10.1016/j.jmr.2013.04.010 · Cited by 59 · see citing works
Berg, A., Norberg, Å., Martling, C., Gamrin, L., Rooyackers, O., & Wernerman, J. (2007) · Intensive Care Medicine · doi:10.1007/s00134-007-0547-9 · Cited by 57 · see citing works
Berg, A., Bellander, B., Wanecek, M., et al. (2006) · Intensive Care Medicine · doi:10.1007/s00134-006-0375-3 · Cited by 57 · see citing works
Xu, T., Mayer, D., Gu, M., et al. (2011) · NMR in Biomedicine · doi:10.1002/nbm.1719 · Cited by 51 · see citing works
Facile Synthesis [5-13C-4-2H2]-L-Glutamine for Hyperpolarized MRS Imaging of Cancer Cell Metabolism
Qü, W., Zha, Z., Lieberman, B. P., Mancuso, A., Stetz, M., Rizzi, R., Plöessl, K., Wise, D. R., Thompson, C. B., & Kung, H. F. (2011) · Academic Radiology · doi:10.1016/j.acra.2011.05.002 · Cited by 37 · see citing works
Self-citationSalamanca-Cardona, L., & Keshari, K. R. (2015) · Cancer & Metabolism · doi:10.1186/s40170-015-0136-2 · Cited by 37 · see citing works
Self-citationWen, H., Cho, H. R., Yun, T., Kim, H., Park, C., Lee, S., Choi, S. H., & Park, S. (2014) · Journal of Neurochemistry · doi:10.1111/jnc.12950 · Cited by 17 · see citing works
High-Throughput Indirect Quantitation of 13C Enriched Metabolites Using 1H NMR
Gialleonardo, V. D., Tee, S. S., Aldeborgh, H. N., Miloushev, V. Z., Cunha, L. S., Sukenick, G. D., & Keshari, K. R. (2016) · Analytical Chemistry · doi:10.1021/acs.analchem.6b03307 · Cited by 17 · see citing works
Self-citationBabakoohi, S., Lapidus, R. G., Faramand, R. G., Sausville, E. A., & Emadi, A. (2016) · Applied immunohistochemistry & molecular morphology · doi:10.1097/pai.0000000000000342 · Cited by 9 · see citing works
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Glutamine reliance in cell metabolism
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- Authors
- Salamanca-Cardona, L., Shah, H., Poot, A. J., Correa, F. M., Di Gialleonardo, V., Lui, H., Miloushev, V. Z., Granlund, K. L., Tee, S. S., Cross, J. R., Thompson, C. B., & Keshari, K. R.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Keshari, Kayvan R.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-12
- Volume
- 26
- Issue
- 6
- Pages
- 830-841.e3
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5718944
- OpenAlex
- W2766586060
- Cited by
- 106
- References
- 50
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 9 · 2023: 12 · 2022: 5 · 2021: 20 · 2020: 15 · 2019: 15 · 2018: 12
- FWCI
- 3.85
- 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
- NIH (R00 EB014328)
- NIH/NCI Cancer Center Support (P30 CA008748)
- Geoffrey Beene Cancer Research Center
- Center for Molecular Imaging and Nanotechnology at MSKCC
- Starr Cancer Consortium grant (I6-A616)
- The Center for Experimental Therapeutics at MSKCC
- Commonwealth Foundation for Cancer Research
- American Italian Cancer Foundation
- 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 › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- 2-hydroxyglutarate, oncometabolites, glutamine metabolism, IDH1 mutation, IDH2 mutation, isocitrate dehydrogenase, chondrosarcoma, IDH1 inhibitor, cancer metabolism, carbon source
- MeSH terms
- Animals, Bone Neoplasms, Chondrosarcoma, Female, Glutamine, Glutarates, Humans, Isocitrate Dehydrogenase, Magnetic Resonance Imaging, Male, Mutation, Biomarkers, Tumor, Mice, SCID, Xenograft Model Antitumor Assays, Cell Line, Tumor
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