The DOI matches its Crossref record; 43 of the 44 references it cites were found in a registry or an index.
SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance
Open accessAbstract
Cancer cells adapt their metabolic processes to support rapid proliferation, but less is known about how cancer cells alter metabolism to promote cell survival in a poorly vascularized tumour microenvironment. Here we identify a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischaemic zones of gliomas. In human glioblastoma multiforme, mitochondrial serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC) are highly expressed in the pseudopalisading cells that surround necrotic foci. We find that SHMT2 activity limits that of pyruvate kinase (PKM2) and reduces oxygen consumption, eliciting a metabolic state that confers a profound survival advantage to cells in poorly vascularized tumour regions. GLDC inhibition impairs cells with high SHMT2 levels as the excess glycine not metabolized by GLDC can be converted to the toxic molecules aminoacetone and methylglyoxal. Thus, SHMT2 is required for cancer cells to adapt to the tumour environment, but also renders these cells sensitive to glycine cleavage system inhibition.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Mitochondrial serine hydroxymethyltransferase (SHMT2) is required for cancer cells to adapt to the tumor environment.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [60]
In the citing paper
“SHMT2 also plays a role in redox balance.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [127]
In the citing paper
“Additionally, expression of SHMT2 promotes survival in the ischemic tumor microenvironment in glioma.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [127]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197
Stem cells, cancer, and cancer stem cells
Reya, T., Morrison, S. J., Clarke, M. F., & Weissman, I. L. (2001) · Nature · doi:10.1038/35102167 · Cited by 9,738
Genome-scale CRISPR-Cas9 knockout screening in human cells
Shalem, O., Sanjana, N. E., Hartenian, E., Shi, X., Scott, D. A., Mikkelsen, T. S., Heckl, D., Ebert, B. L., Root, D. E., Doench, J. G., et al. (2014) · Science · doi:10.1126/science.1247005 · Cited by 5,234
ONCOMINE: A Cancer Microarray Database and Integrated Data-Mining Platform
Rhodes, D. R., Yu, J., Sundaram, S. K., Deshpande, N., Varambally, R., Ghosh, D., Barrette, T. R., Pander, A., & Chinnaiyan, A. M. (2004) · Neoplasia · doi:10.1016/s1476-5586(04)80047-2 · Cited by 3,719
Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation
Lunt, S. Y., & Vander Heiden, M. G. (2011) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-092910-154237 · Cited by 3,057
Genetic screens in human cells using the CRISPR-Cas9 system
Wang, T., Wei, J. J., Sabatini, D. M., & Lander, E. S. (2014) · Science · doi:10.1126/science.1246981 · Cited by 2,856
Self-citationExploiting tumour hypoxia in cancer treatment
Brown, J. M., & Wilson, W. R. (2004) · Nature Reviews Cancer · doi:10.1038/nrc1367 · Cited by 2,828
The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth
Christofk, H. R., Vander Heiden, M. G., Harris, M. H., Ramanathan, A., Gerszten, R. E., Wei, R., Fleming, M. D., Schreiber, S. L., & Cantley, L. C. (2008) · Nature · doi:10.1038/nature06734 · Cited by 2,820
Lee, J., Kotliarova, S. E., Kotliarov, Y., Li, A., Su, Q., Donin, N. M., Pastorino, S., Purow, B. W., Christopher, N., Zhang, W., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.03.030 · Cited by 2,345
HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption
Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L., & Denko, N. C. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.01.012 · Cited by 2,267
Functional genomics reveal that the serine synthesis pathway is essential in breast cancer
Possemato, R., Marks, K. M., Shaul, Y. D., Pacold, M. E., Kim, D., Birsoy, K., Sethumadhavan, S., Woo, H.-K., Jang, H. G., Jha, A. K., et al. (2011) · Nature · doi:10.1038/nature10350 · Cited by 1,683
Self-citationMetabolite profiling identifies a key role for glycine in rapid cancer cell proliferation
Jain, M., Nilsson, R., Sharma, S., Madhusudhan, N., Kitami, T., Souza, A. L., Kafri, R., Kirschner, M. W., Clish, C. B., & Mootha, V. K. (2012) · Science · doi:10.1126/science.1218595 · Cited by 1,403
Anastasiou, D., Poulogiannis, G., Asara, J. M., Boxer, M. B., Jiang, J., Shen, M., Bellinger, G., Sasaki, A. T., Locasale, J. W., Auld, D. S., et al. (2011) · Science · doi:10.1126/science.1211485 · Cited by 1,218
Targeting metabolic transformation for cancer therapy
Tennant, D. A., Durán, R. V., & Gottlieb, E. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2817 · Cited by 1,073
Cancer Cell Metabolism: One Hallmark, Many Faces
Cantor, J. R., & Sabatini, D. M. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0345 · Cited by 989
Self-citationFolate and homocysteine metabolism in neural plasticity and neurodegenerative disorders
Mattson, M. P., & Shea, T. B. (2003) · Trends in Neurosciences · doi:10.1016/s0166-2236(03)00032-8 · Cited by 847
Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis
Anastasiou, D., Yu, Y., Israelsen, W. J., Jiang, J.-K., Boxer, M. B., Hong, B. S., Tempel, W., Dimov, S., Shen, M., Jha, A., et al. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.1060 · Cited by 816
Self-citationCompartmentalization of Mammalian Folate-Mediated One-Carbon Metabolism
Tibbetts, A. S., & Appling, D. R. (2010) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.012809.104810 · Cited by 692
Serine is a natural ligand and allosteric activator of pyruvate kinase M2
Chaneton, B., Hillmann, P., Zheng, L., Martin, A. C. L., Maddocks, O. D. K., Chokkathukalam, A., Coyle, J. E., Jankevics, A., Holding, F. P., Vousden, K. H., et al. (2012) · Nature · doi:10.1038/nature11540 · Cited by 661
Zhang, W. C., Shyh-Chang, N., Yang, H., Rai, A., Umashankar, S., Ma, S., Soh, B. S., Sun, L. L., Tai, B. C., Nga, M. E., et al. (2012) · Cell · doi:10.1016/j.cell.2011.11.050 · Cited by 660
Rong, Y., Durden, D. L., Meir, E. G. V., & Brat, D. J. (2006) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-200606000-00001 · Cited by 584
Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells
Labuschagne, C. F., van den Broek, N. J. F., Mackay, G. M., Vousden, K. H., & Maddocks, O. D. K. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.04.045 · Cited by 576
Malignant Glioma: Lessons from Genomics, Mouse Models, and Stem Cells
Chen, J., McKay, R. M., & Parada, L. F. (2012) · Cell · doi:10.1016/j.cell.2012.03.009 · Cited by 549
Highly parallel identification of essential genes in cancer cells
Luo, B., Cheung, H. W., Subramanian, A., Sharifnia, T., Okamoto, M., Yang, X., Hinkle, G., Boehm, J. S., Beroukhim, R., Weir, B. A., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810485105 · Cited by 541
Self-citationMethylglyoxal in living organisms
Kalapos, M. P. (1999) · Toxicology Letters · doi:10.1016/s0378-4274(99)00160-5 · Cited by 507
Brat, D. J., & Meir, E. G. V. (2004) · Laboratory Investigation · doi:10.1038/labinvest.3700070 · Cited by 335
Hypoxia and defective apoptosis drive genomic instability and tumorigenesisPreprint
Nelson, D. A., Tan, T.-T., Rabson, A. B., Anderson, D., Degenhardt, K., & White, E. (2004) · Genes & Development · doi:10.1101/gad.1204904 · Cited by 284
Keller, K. E., Tan, I. S., & Lee, Y.-S. (2012) · Science · doi:10.1126/science.1224409 · Cited by 228
Rotem, R., Heyfets, A., Fingrut, O., Blickstein, D., Shaklai, M., & Flescher, E. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-3091 · Cited by 192
Saudubray, J., Baumgartner, M. R., & Walter, J. H. (2011) · Springer eBooks · doi:10.1007/978-3-642-15720-2 · Cited by 180
Mehta, S. V., Huillard, E., Kesari, S., Maire, C. L., Golebiowski, D., Harrington, E. P., Alberta, J. A., Kane, M., Theisen, M., Ligon, K. L., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.01.035 · Cited by 165
Self-citationKami, K., Fujimori, T., Sato, H., Sato, M., Yamamoto, H., Ohashi, Y., Sugiyama, N., Ishihama, Y., Onozuka, H., Ochiai, A., et al. (2012) · Metabolomics · doi:10.1007/s11306-012-0452-2 · Cited by 148
Self-citationChudnovsky, Y., Kim, D., Zheng, S., Whyte, W. A., Bansal, M., Bray, M.-A., Gopal, S., Theisen, M. A., Bilodeau, S., Thiru, P., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2013.12.032 · Cited by 136
Self-citationAllosteric Regulation of PKM2 Allows Cellular Adaptation to Different Physiological States
Gui, D. Y., Lewis, C. A., & Heiden, M. G. V. (2013) · Science Signaling · doi:10.1126/scisignal.2003925 · Cited by 124
Self-citationDale, R. A. (1978) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/0304-4165(78)90324-0 · Cited by 86
Tressel, T., Thompson, R., Zieske, L. R., Menendez, M. I., & Davis, L. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)66584-6 · Cited by 81
Narkewicz, M. R., SAULS, S. D., Tjoa, S., Teng, C. C., & Fennessey, P. V. (1996) · Biochemical Journal · doi:10.1042/bj3130991 · Cited by 73
Regulation of Hepatic Glycine Catabolism by Glucagon
Jois, M., Hall, B., Fewer, K., & Brosnan, J. T. (1989) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)94072-x · Cited by 34
Sartori, A., Garay-Malpartida, M., Forni, M. F., Schumacher, R. I., Dutra, F., Sogayar, M. C., & Bechara, E. J. H. (2008) · Chemical Research in Toxicology · doi:10.1021/tx8001753 · Cited by 32
Kazachkov, M., & Yu, P. (2005) · Journal of Chromatography B · doi:10.1016/j.jchromb.2005.07.006 · Cited by 27
Xiao, S., & Yu, P. H. (2008) · Analytical Biochemistry · doi:10.1016/j.ab.2008.09.029 · Cited by 22
Shikano, N., Ogura, M., Sagara, J., Nakajima, S., Kobayashi, M., Baba, T., Yamaguchi, N., Iwamura, Y., Kubota, N., & Kawai, K. (2010) · Nuclear Medicine and Biology · doi:10.1016/j.nucmedbio.2009.10.003 · Cited by 7
A 9-Month-Old Boy with Seizures and Discrepant Urine Tryptophan Concentrations
Ptolemy, A. S., Li, Y., Sanderson, T., Khwaja, O., Berry, G. T., & Kellogg, M. D. (2011) · Clinical Chemistry · doi:10.1373/clinchem.2010.144899 · Cited by 5
Cited by
Sorted by citations
Fundamentals of Cancer Metabolism
DeBerardinis, R. J., & Chandel, N. S. (2016) · Science Advances · doi:10.1126/sciadv.1600200 · Cited by 3,013
Metabolomics: beyond biomarkers and towards mechanisms
Johnson, C. H., Ivanisevic, J., & Siuzdak, G. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.25 · Cited by 2,829
One-Carbon Metabolism in Health and Disease
Ducker, G. S., & Rabinowitz, J. D. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2016.08.009 · Cited by 2,239
Vyas, S., Zaganjor, E., & Haigis, M. C. (2016) · Cell · doi:10.1016/j.cell.2016.07.002 · Cited by 1,735
Zong, W., Rabinowitz, J. D., & White, E. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.02.011 · Cited by 1,330
Metadata
- Authors
- Kim, D., Fiske, B. P., Birsoy, K., Freinkman, E., Kami, K., Possemato, R. L., Chudnovsky, Y., Pacold, M. E., Chen, W. W., Cantor, J. R., Shelton, L. M., Gui, D. Y., Kwon, M., Ramkissoon, S. H., Ligon, K. L., Kang, S. W., Snuderl, M., Vander Heiden, M. G., & Sabatini, D. M.
- Affiliations
- Broad Institute (US)
- Human Metabolome Technologies, Inc. (Japan) (JP)
- Whitehead Institute for Biomedical Research (US)
- Brigham and Women's Hospital (US)
- NYU Langone Health (US)
- Corresponding author
- Sabatini, David M.
- ORCID
- Venue
- Nature
- Published
- 2015-04
- Volume
- 520
- Issue
- 7547
- Pages
- 363-367
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4533874
- OpenAlex
- W1993238514
- Cited by
- 368
- References
- 44
- Citations by year
- 2026: 25 · 2025: 22 · 2024: 21 · 2023: 28 · 2022: 41 · 2021: 42 · 2020: 25 · 2019: 39 · 2018: 34 · 2017: 30 · 2016: 42 · 2015: 18
- FWCI
- 13.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Radboud Repository (Radboud University) (submittedVersion)
- PMC
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (5-P30-CA14051, CA129105, K99CA168940, CA103866, R01CA103866, R01CA168653, R01CA129105, R00CA168940, P30CA014051)
- National Institute of General Medical Sciences (T32GM007753, T32GM007287)
- National Institute of Allergy and Infectious Diseases (AI-07389, T32AI007389, R37AI047389)
- National Institute of Neurological Disorders and Stroke (K08NS087118)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- SHMT2, glycine decarboxylase, glioblastoma, serine metabolism, glycine metabolism, oxygen consumption, PKM2, methylglyoxal, aminoacetone, tumor cell survival, tumor hypoxia
- MeSH terms
- Acetone, Animals, Brain Neoplasms, Cell Survival, Female, Glioblastoma, Glycine, Humans, Ischemia, Necrosis, Oxygen Consumption, Pyruvaldehyde, Pyruvate Kinase, Glycine Hydroxymethyltransferase, Cell Hypoxia, Xenograft Model Antitumor Assays, Cell Line, Tumor, Glycine Dehydrogenase (Decarboxylating), Mice, Tumor Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
