Functional genomics reveal that the serine synthesis pathway is essential in breast cancer
Open accessAbstract
Cancer cells adapt their metabolic processes to drive macromolecular biosynthesis for rapid cell growth and proliferation. RNA interference (RNAi)-based loss-of-function screening has proven powerful for the identification of new and interesting cancer targets, and recent studies have used this technology in vivo to identify novel tumour suppressor genes. Here we developed a method for identifying novel cancer targets via negative-selection RNAi screening using a human breast cancer xenograft model at an orthotopic site in the mouse. Using this method, we screened a set of metabolic genes associated with aggressive breast cancer and stemness to identify those required for in vivo tumorigenesis. Among the genes identified, phosphoglycerate dehydrogenase (PHGDH) is in a genomic region of recurrent copy number gain in breast cancer and PHGDH protein levels are elevated in 70% of oestrogen receptor (ER)-negative breast cancers. PHGDH catalyses the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased serine synthesis flux. Suppression of PHGDH in cell lines with elevated PHGDH expression, but not in those without, causes a strong decrease in cell proliferation and a reduction in serine synthesis. We find that PHGDH suppression does not affect intracellular serine levels, but causes a drop in the levels of α-ketoglutarate, another output of the pathway and a tricarboxylic acid (TCA) cycle intermediate. In cells with high PHGDH expression, the serine synthesis pathway contributes approximately 50% of the total anaplerotic flux of glutamine into the TCA cycle. These results reveal that certain breast cancers are dependent upon increased serine pathway flux caused by PHGDH overexpression and demonstrate the utility of in vivo negative-selection RNAi screens for finding potential anticancer targets.
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
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?
PHGDH expression and increased serine biosynthesis are important for supporting cancer cell proliferation and survival in both in vitro and in vivo settings.
“Serine is present in plasma and can be taken up by cells via amino acid transporters, yet PHGDH expression and increased serine biosynthesis have been shown to be important for supporting cancer cell proliferation and survival in both in vitro and in vivo settings (Locasale et al., 2011; Possemato et al., 2011).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Possemato et al., 2011
Functional PHGDH loss is toxic to tumor cells with PHGDH amplification or high serine biosynthetic flux.
“Functional PHGDH loss is toxic to tumor cells with PHGDH amplification or high serine biosynthetic flux (Locasale et al., 2011; Mattaini et al., 2015; Possemato et al., 2011; Zhang et al., 2017), and small-molecule inhibitors targeting PHGDH have been shown to inhibit serine synthesis and tumor proliferation in vitro and in xenograft cancer models (Mullarky et al., 2016; Pacold et al., 2016; Wang”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Possemato et al., 2011
Increased PHGDH expression leads to greater production of serine from glucose and is associated with specific subsets of breast cancer, lung adenocarcinoma, and melanoma.
“Increased PHGDH gene expression leads to greater production of serine from glucose and is associated with specific subsets of breast cancer, lung adenocarcinoma, and melanoma (Locasale et al., 2011; Possemato et al., 2011; Zhang et al., 2017).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Possemato et al., 2011
Increased PHGDH expression in some cancers can result from copy number gain of a region on chromosome 1p or from oncogenic signaling including NRF2 and ATF4 signaling or hypoxia responses.
“More recently, it was found that increased expression of the serine synthesis enzyme phosphoglycerate dehydrogenase (PHGDH) in some cancers can result from copy number gain of a region on chromosome 1p (Beroukhim et al., 2010; Locasale et al., 2011; Possemato et al., 2011) or a consequence of oncogenic signaling, including NRF2 and ATF4 signaling (DeNicola et al., 2015), or hypoxia responses (Sam”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Possemato et al., 2011
PHGDH is frequently focally amplified in breast cancer and melanoma and is required for growth of PHGDH-amplified cells in vitro and in vivo.
“A rate-limiting serine biosynthesis enzyme, 3-phosphoglycerate dehydrogenase (PHGDH), is frequently focally amplified in breast cancer and melanoma and is required for the growth of PHGDH-amplified cells in vitro as well as in vivo”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Possemato et al., 2011
Increased PHGDH expression can promote enhanced serine biosynthesis and the proliferation of cancer cells.
“Amplification of PHGDH has been observed in breast cancer and melanoma (65), and increased PHGDH expression can promote both enhanced serine biosynthesis and the proliferation of cancer cells (65, 66).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [66]
The region of chromosome 1p12 encoding PHGDH is amplified in a significant fraction of tumors.
“the region of chromosome 1p12 encoding PHGDH is amplified in a significant fraction of tumors”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Possemato et al., 2011
Cell lines derived from tumors with PHGDH amplification tend to be highly dependent on PHGDH expression.
“cell lines derived from these tumors tend to be highly dependent on PHGDH expression”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Possemato et al., 2011
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
A Gene-Expression Signature as a Predictor of Survival in Breast Cancer
van de Vijver, M. J., He, Y. D., Veer, L. V. ‘., Dai, H. A., Hart, A. A. M., Voskuil, D. W., Schreiber, G. J., Peterse, J. L., Roberts, C., Marton, M. J., et al. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa021967 · Cited by 6,411 · see citing works
The landscape of somatic copy-number alteration across human cancers
Beroukhim, R., Mermel, C. H., Porter, D., Wei, G., Raychaudhuri, S., Donovan, J., Barretina, J., Boehm, J. S., Dobson, J., Urashima, M., et al. (2010) · Nature · doi:10.1038/nature08822 · Cited by 4,017 · see citing works
Self-citationDeBerardinis, 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
Ben‐Porath, I., Thomson, M., Carey, V. J., Ge, R., Bell, G. W., Regev, A., & Weinberg, R. A. (2008) · Nature Genetics · doi:10.1038/ng.127 · Cited by 2,523 · see citing works
Sancak, Y., Bar-Peled, L., Zoncu, R., Markhard, A. L., Nada, S., & Sabatini, D. M. (2010) · Cell · doi:10.1016/j.cell.2010.02.024 · Cited by 2,464 · see citing works
Self-citationCancer cell metabolism: warburg and beyond
Hsu, P. P., & Sabatini, D. M. (2008) · Cell · doi:10.1016/j.cell.2008.08.021 · Cited by 2,452 · see citing works
Self-citationRhodes, D. R., Sundaram, S. K., Mahavisno, V., Varambally, R., Yu, J., Briggs, B., Barrette, T. R., Anstett, M. J., Kincead-Beal, C., Kulkarni, P., et al. (2007) · Neoplasia · doi:10.1593/neo.07112 · Cited by 2,064 · see citing works
A Lentiviral RNAi Library for Human and Mouse Genes Applied to an Arrayed Viral High-Content Screen
Moffat, J., Grueneberg, D. A., Yang, X., Kim, S. Y., Kloepfer, A. M., Hinkle, G., Piqani, B., Eisenhaure, T., Luo, B., Grenier, J. K., et al. (2006) · Cell · doi:10.1016/j.cell.2006.01.040 · Cited by 1,803 · see citing works
Self-citationDissecting direct reprogramming through integrative genomic analysis
Mikkelsen, T. S., Hanna, J. H., Zhang, X., Ku, M., Wernig, M., Schorderet, P., Bernstein, B., Jaenisch, R., Lander, E. S., & Meissner, A. (2008) · Nature · doi:10.1038/nature07056 · Cited by 1,472 · see citing works
Connecting microRNA Genes to the Core Transcriptional Regulatory Circuitry of Embryonic Stem Cells
Marson, A., Levine, S. S., Cole, M. F., Frampton, G. M., Brambrink, T., Johnstone, S. E., Guenther, M. G., Johnston, W. K., Wernig, M., Newman, J. J., et al. (2008) · Cell · doi:10.1016/j.cell.2008.07.020 · Cited by 1,361 · see citing works
An Extended Transcriptional Network for Pluripotency of Embryonic Stem Cells
Kim, J., Chu, J., Shen, X., Wang, J., & Orkin, S. H. (2008) · Cell · doi:10.1016/j.cell.2008.02.039 · Cited by 1,321 · see citing works
Tumor suppressors and cell metabolism: a recipe for cancer growth
Jones, R. G., & Thompson, C. B. (2009) · Genes & Development · doi:10.1101/gad.1756509 · Cited by 1,085 · see citing works
Modelling glandular epithelial cancers in three-dimensional cultures
Debnath, J., & Brugge, J. S. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1695 · Cited by 1,014 · see citing works
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 · see citing works
Self-citationTumours with PI3K activation are resistant to dietary restriction
Kalaany, N. Y., & Sabatini, D. M. (2009) · Nature · doi:10.1038/nature07782 · Cited by 468 · see citing works
Self-citationSingle-vector inducible lentiviral RNAi system for oncology target validation
Wiederschain, D., Susan, W. N., Chen, L., Loo, A. T., Yang, G., Huang, A., Chen, Y., Caponigro, G., Yao, Y.-M., Christoph Lengauer, C., et al. (2009) · Cell Cycle · doi:10.4161/cc.8.3.7701 · Cited by 441 · see citing works
MCF10DCIS.com Xenograft Model of Human Comedo Ductal Carcinoma In Situ
Miller, F. R., Santner, S. J., Tait, L. R., & Dawson, P. J. (2000) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/92.14.1185a · Cited by 344 · see citing works
Buescher, J. M., Moco, S., Sauer, U., & Zamboni, N. (2010) · Analytical Chemistry · doi:10.1021/ac100101d · Cited by 341 · see citing works
Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis
Pollari, S., Käkönen, S.-M., Edgren, H., Wolf, M., Kohonen, P., Sara, H., Guise, T., Nees, M., & Kallioniemi, O. (2011) · Breast Cancer Research and Treatment · doi:10.1007/s10549-010-0848-5 · Cited by 269 · see citing works
Enzymes of serine metabolism in normal, developing and neoplastic rat tissues
Snell, K. (1984) · Advances in Enzyme Regulation · doi:10.1016/0065-2571(84)90021-9 · Cited by 267 · cited 3× · see citing works
“Classic studies show elevated serine biosynthetic activity, as determined by enzyme assays, in rat tumour lysates (10, 13), and suggest that PSPH is the rate-limiting enzyme of this pathway in the liver (14).”
Xenograft Model of Progressive Human Proliferative Breast Disease
Miller, F. R., Soule, H. D., Tait, L. R., Pauley, R. J., Wolman, S. R., Dawson, P. J., & Heppner, G. H. (1993) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/85.21.1725 · Cited by 206 · see citing works
Bric, A., Miething, C., Bialucha, C. U., Scuoppo, C., Zender, L., Krasnitz, A., Xuan, Z., Zuber, J. A., Wigler, M. H., Hicks, J. B., et al. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.08.015 · Cited by 160 · see citing works
Cloning, sequencing and expression of rat liver 3-phosphoglycerate dehydrogenase
Achouri, Y., Rider, M. H., SCHAFTINGEN, E. V., & Robbi, M. (1997) · Biochemical Journal · doi:10.1042/bj3230365 · Cited by 93 · see citing works
Purification and Properties of Chicken Liver D-3-Phosphoglycerate Dehydrogenase*
Walsh, D. A., & Sallach, H. J. (1965) · Biochemistry · doi:10.1021/bi00882a015 · Cited by 65 · see citing works
Phosphoserine phosphatase distribution in normal and neoplastic rat tissues
Knox, W. E., Herzfeld, A., & Hudson, J. (1969) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(69)90381-6 · Cited by 38 · see citing works
Lund, K., Merrill, D. K., & Guynn, R. W. (1985) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(85)90268-1 · Cited by 33 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The emerging hallmarks of cancer metabolism
Pavlova, N. N., & Thompson, C. B. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.006 · Cited by 5,926 · see citing works
Modulation of oxidative stress as an anticancer strategy
Gorrini, C., Harris, I. S., & Mak, T. W. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4002 · Cited by 3,579 · see citing works
Metabolic 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
Fundamentals of Cancer Metabolism
DeBerardinis, R. J., & Chandel, N. S. (2016) · Science Advances · doi:10.1126/sciadv.1600200 · Cited by 3,013 · see citing works
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 · see citing works
From Krebs to clinic: glutamine metabolism to cancer therapy
Altman, B. J., Stine, Z. E., & Dang, C. V. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.71 · Cited by 2,119 · see citing works
Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism
Ying, H., Kimmelman, A. C., Lyssiotis, C. A., Hua, S., Chu, G. C., Fletcher-Sananikone, E., Locasale, J. W., Son, J., Zhang, H., Coloff, J. L., et al. (2012) · Cell · doi:10.1016/j.cell.2012.01.058 · Cited by 2,043 · see citing works
Drugging the undruggable RAS: Mission Possible?
Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J., & Der, C. J. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4389 · Cited by 1,997 · see citing works
L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity
Geiger, R., Rieckmann, J. C., Wolf, T., Basso, C., Feng, Y., Fuhrer, T., Kogadeeva, M., Picotti, P., Meissner, F., Mann, M., et al. (2016) · Cell · doi:10.1016/j.cell.2016.09.031 · Cited by 1,775 · see citing works
Cancer metabolism: a therapeutic perspective
Martinez-Outschoorn, U. E., Peiris-Pagés, M., Pestell, R. G., Sotgia, F., & Lisanti, M. P. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.60 · Cited by 1,505 · see citing works
The hallmarks of cancer metabolism: still emerging
Pavlova, N. N., Zhu, J., & Thompson, C. B. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.01.007 · Cited by 1,418 · see citing works
Metabolite 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 · see citing works
Fueling Immunity: Insights into Metabolism and Lymphocyte Function
Pearce, E. L., Poffenberger, M. C., Chang, C.-H., & Jones, R. G. (2013) · Science · doi:10.1126/science.1242454 · Cited by 1,363 · see citing works
Oxidative stress inhibits distant metastasis by human melanoma cells
Piskounova, E., Agathocleous, M., Murphy, M. M., Hu, Z., Huddlestun, S. E., Zhao, Z., Leitch, A. M., Johnson, T. M., DeBerardinis, R. J., & Morrison, S. J. (2015) · Nature · doi:10.1038/nature15726 · Cited by 1,269 · see citing works
Metabolic heterogeneity in human lung tumors
Hensley, C. T., Faubert, B., Yuan, Q., Lev-Cohain, N., Jin, E., Kim, J., Jiang, L., Ko, B., Skelton, R., Loudat, L., et al. (2016) · Cell · doi:10.1016/j.cell.2015.12.034 · Cited by 1,138 · see citing works
Quantitative flux analysis reveals folate-dependent NADPH production
Fan, J., Ye, J., Kamphorst, J. J., Shlomi, T., Thompson, C. B., & Rabinowitz, J. D. (2014) · Nature · doi:10.1038/nature13236 · Cited by 1,114 · see citing works
Glucose-Independent Glutamine Metabolism via TCA Cycling for Proliferation and Survival in B Cells
Le, A., Lane, A. N., Hamaker, M., Bose, S., Gouw, A., Barbi, J., Tsukamoto, T., Rojas, C. J., Slusher, B. S., Zhang, H., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2011.12.009 · Cited by 1,095 · see citing works
Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells
Maddocks, O. D. K., Berkers, C. R., Mason, S. M., Zheng, L., Blyth, K., Gottlieb, E., & Vousden, K. H. (2013) · Nature · doi:10.1038/nature11743 · Cited by 1,007 · see citing works
Targeting Metabolism for Cancer Therapy
Luengo, A., Gui, D. Y., & Vander Heiden, M. G. (2017) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.08.028 · Cited by 971 · see citing works
Serine and one-carbon metabolism in cancer
Yang, M., & Vousden, K. H. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.81 · Cited by 992 · see citing works
Regulation of mammalian nucleotide metabolism and biosynthesis
Lane, A. N., & Fan, T. W.-M. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv047 · Cited by 959 · see citing works
Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us?
DeBerardinis, R. J., & Thompson, C. B. (2012) · Cell · doi:10.1016/j.cell.2012.02.032 · Cited by 858 · see citing works
NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis
Alvarez, S. W., Sviderskiy, V. O., Terzi, E. M., Papagiannakopoulos, T., Moreira, A. L., Adams, S., Sabatini, D. M., Birsoy, K., & Possemato, R. (2017) · Nature · doi:10.1038/nature24637 · Cited by 787 · see citing works
Self-citationMetabolic determinants of cancer cell sensitivity to glucose limitation and biguanides
Birsoy, K., Possemato, R., Lorbeer, F. K., Bayraktar, E. C., Thiru, P., Yucel, B., Wang, T., Chen, W. W., Clish, C. B., & Sabatini, D. M. (2014) · Nature · doi:10.1038/nature13110 · Cited by 710 · see citing works
Self-citationMetabolic Regulation of Epigenetics
Lu, C., & Thompson, C. B. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.06.001 · Cited by 699 · see citing works
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 · see citing works
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 · see citing works
Metabolites and the Tumour Microenvironment: From Cellular Mechanisms to Systemic Metabolism
Elia, I., & Haigis, M. C. (2021) · Nature Metabolism · doi:10.1038/s42255-020-00317-z · Cited by 651 · see citing works
Influence of Threonine Metabolism on <i>S</i> -Adenosylmethionine and Histone Methylation
Shyh-Chang, N., Locasale, J. W., Lyssiotis, C. A., Zheng, Y., Teo, R. Y., Ratanasirintrawoot, S., Zhang, J., Onder, T., Unternaehrer, J. J., Zhu, H., et al. (2013) · Science · doi:10.1126/science.1226603 · Cited by 638 · see citing works
Serine is an essential metabolite for effector T cell expansion
Ma, E. H., Bantug, G., Griss, T., Condotta, S., Johnson, R. M., Samborska, B., Mainolfi, N., Suri, V., Guak, H., Balmer, M. L., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2016.12.011 · Cited by 657 · see citing works
Modulating the therapeutic response of tumours to dietary serine and glycine starvation
Maddocks, O. D. K., Athineos, D., Cheung, E. C., Lee, P., Zhang, T., van den Broek, N. J. F., Mackay, G. M., Labuschagne, C. F., Gay, D., Kruiswijk, F., et al. (2017) · Nature · doi:10.1038/nature22056 · Cited by 603 · see citing works
Mechanisms and Implications of Metabolic Heterogeneity in Cancer
Kim, J., & DeBerardinis, R. J. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.08.013 · Cited by 606 · see citing works
Sullivan, M. R., Danai, L. V., Lewis, C. A., Chan, S. H., Gui, D. Y., Kunchok, T., Dennstedt, E. A., Vander Heiden, M. G., & Muir, A. (2019) · eLife · doi:10.7554/elife.44235 · Cited by 588 · see citing works
A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate
Pacold, M. E., Brimacombe, K. R., Chan, S. H., Rohde, J. M., Lewis, C. A., Swier, L. J. Y. M., Possemato, R., Chen, W. W., Sullivan, L. B., Fiske, B. P., et al. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2070 · Cited by 553 · see citing works
Self-citationSerine, 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 · see citing works
Nilsson, R., Jain, M., Madhusudhan, N., Sheppard, N. G., Strittmatter, L., Kampf, C., Huang, J., Asplund, A., & Mootha, V. K. (2014) · Nature Communications · doi:10.1038/ncomms4128 · Cited by 607 · see citing works
The mTORC1 Pathway Stimulates Glutamine Metabolism and Cell Proliferation by Repressing SIRT4
Csibi, A., Fendt, S.-M., Li, C., Poulogiannis, G., Choo, A. Y., Chapski, D. J., Jeong, S. M., Dempsey, J. M., Parkhitko, A., Morrison, T., et al. (2013) · Cell · doi:10.1016/j.cell.2013.04.023 · Cited by 586 · see citing works
PKM2, cancer metabolism, and the road ahead
Dayton, T. L., Jacks, T., & Vander Heiden, M. G. (2016) · The EMBO Reports · doi:10.15252/embr.201643300 · Cited by 515 · see citing works
Fructose-1,6-bisphosphatase opposes renal carcinoma progression
Li, B., Qiu, B., Lee, D. S. M., Walton, Z. E., Ochocki, J. D., Mathew, L. K., Mancuso, A., Gade, T. P. F., Keith, B., Nissim, I., et al. (2014) · Nature · doi:10.1038/nature13557 · Cited by 535 · see citing works
Pyruvate carboxylase is critical for non–small-cell lung cancer proliferation
Sellers, K., Fox, M. P., Bousamra, M., Slone, S. P., Higashi, R. M., Miller, D. M., Wang, Y., Yan, J., Yuneva, M. O., Deshpande, R., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci72873 · Cited by 497 · see citing works
BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1
Tönjes, M., Barbus, S., Park, Y. J., Wang, W., Schlotter, M., Lindroth, A. M., Pleier, S. V., Bai, A. H. C., Karra, D., Piro, R. M., et al. (2013) · Nature Medicine · doi:10.1038/nm.3217 · Cited by 486 · see citing works
Lin28: Primal Regulator of Growth and Metabolism in Stem Cells
Shyh-Chang, N., & Daley, G. Q. (2013) · Cell Stem Cell · doi:10.1016/j.stem.2013.03.005 · Cited by 458 · see citing works
Tumor glycolysis, an essential sweet tooth of tumor cells
Paul, S., Ghosh, S., & Kumar, S. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.09.007 · Cited by 449 · see citing works
Serine Catabolism Regulates Mitochondrial Redox Control during Hypoxia
Ye, J., Fan, J., Venneti, S., Wan, Y.-W., Pawel, B. R., Zhang, J., Finley, L. W. S., Lu, C., Lindsten, T., Cross, J. R., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0250 · Cited by 452 · see citing works
Reversal of cytosolic one-carbon flux compensates for loss of the mitochondrial folate pathway
Ducker, G. S., Chen, L., Morscher, R. J., Ghergurovich, J. M., Esposito, M., Teng, X., Kang, Y., & Rabinowitz, J. D. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.04.016 · Cited by 419 · see citing works
MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis
Terunuma, A., Putluri, N., Mishra, P., Mathé, E. A., Dorsey, T. H., Yi, M., Wallace, T. A., Issaq, H. J., Zhou, M., Killian, J. K., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci71180 · Cited by 428 · see citing works
Daemen, A., Peterson, D., Sahu, N., McCord, R., Du, X., Liu, B., Kowanetz, K., Hong, R., Moffat, J., Gao, M., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1501605112 · Cited by 398 · see citing works
Cancer metabolism: current perspectives and future directions
Muñoz-Pinedo, C., El Mjiyad, N., & Ricci, J.-E. (2012) · Cell Death & Disease · doi:10.1038/cddis.2011.123 · Cited by 385 · see citing works
LKB1 loss links serine metabolism to DNA methylation and tumorigenesis
Kottakis, F., Nicolay, B. N., Roumane, A., Karnik, R., Gu, H., Nagle, J. M., Boukhali, M., Hayward, M. C., Li, Y. Y., Chen, T., et al. (2016) · Nature · doi:10.1038/nature20132 · Cited by 348 · see citing works
SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance
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., et al. (2015) · Nature · doi:10.1038/nature14363 · Cited by 368 · see citing works
Self-citationPassenger deletions generate therapeutic vulnerabilities in cancer
Muller, F. L., Colla, S., Aquilanti, E., Manzo, V. E., Genovese, G., Lee, J., Eisenson, D., Narurkar, R., Deng, P., Nezi, L., et al. (2012) · Nature · doi:10.1038/nature11331 · Cited by 339 · see citing works
Wei, L., Lee, D., Law, C.-T., Zhang, M. S., Shen, J., Chin, D. W.-C., Zhang, A., Tsang, F. H.-C., Wong, C. L.-S., Ng, I. O.-L., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12606-7 · Cited by 428 · see citing works
Mullarky, E., Lucki, N. C., Beheshti Zavareh, R., Anglin, J. L., Gomes, A. P., Nicolay, B. N., Wong, J. C. Y., Christen, S., Takahashi, H., Singh, P. K., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1521548113 · Cited by 333 · see citing works
Metabolism of [U‐ <sup>13</sup> C]glucose in human brain tumors <i>in vivo</i>
Maher, E. A., Marin‐Valencia, I., Bachoo, R. M., Mashimo, T., Raisanen, J., Hatanpaa, K. J., Jindal, A., Jeffrey, F. M., Choi, C., Madden, C., et al. (2012) · NMR in Biomedicine · doi:10.1002/nbm.2794 · Cited by 341 · see citing works
Metabolic signatures of cancer cells and stem cells
Intlekofer, A. M., & Finley, L. W. S. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0032-0 · Cited by 322 · see citing works
Valencia, T., Kim, J. Y., Abu-Baker, S., Moscat-Pardos, J., Ahn, C. S., Reina-Campos, M., Duran, A., Castilla, E. A., Metallo, C. M., Diaz-Meco, M. T., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.05.004 · Cited by 304 · see citing works
Differential Glutamate Metabolism in Proliferating and Quiescent Mammary Epithelial Cells
Coloff, J. L., Murphy, J. P., Braun, C. R., Harris, I. S., Shelton, L. M., Kami, K., Gygi, S. P., Selfors, L. M., & Brugge, J. S. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.03.016 · Cited by 288 · see citing works
BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival
Gorrini, C., Baniasadi, P. S., Harris, I. S., Silvester, J., Inoue, S., Snow, B., Joshi, P. A., Wakeham, A., Molyneux, S. D., Martin, B., et al. (2013) · Journal of Experimental Medicine · doi:10.1084/jem.20121337 · Cited by 289 · see citing works
Lin, R., Elf, S., Shan, C., Kang, H.-B., Ji, Q., Zhou, L., Hitosugi, T., Zhang, L., Zhang, S., Seo, J. H., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3255 · Cited by 287 · see citing works
Serine in plants: biosynthesis, metabolism, and functions
Ros, R., Muñoz-Bertomeu, J., & Krueger, S. (2014) · Trends in Plant Science · doi:10.1016/j.tplants.2014.06.003 · Cited by 279 · see citing works
The Influence of Metabolism on Drug Response in Cancer
Zaal, E. A., & Berkers, C. R. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00500 · Cited by 272 · see citing works
L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH
Intlekofer, A. M., Wang, B., Liu, H., Shah, H., Carmona-Fontaine, C., Rustenburg, A. S., Salah, S., Gunner, M. R., Chodera, J. D., Cross, J. R., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2307 · Cited by 268 · see citing works
Ducker, G. S., Ghergurovich, J. M., Mainolfi, N., Suri, V., Jeong, S. K., Hsin-Jung Li, S., Friedman, A., Manfredi, M. G., Gitai, Z., Kim, H., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1706617114 · Cited by 261 · see citing works
Chemical Proteomics Identifies Druggable Vulnerabilities in a Genetically Defined Cancer
Bar-Peled, L., Kemper, E. K., Suciu, R. M., Vinogradova, E. V., Backus, K. M., Horning, B. D., Paul, T. A., Ichu, T.-A., Svensson, R. U., Olucha, J., et al. (2017) · Cell · doi:10.1016/j.cell.2017.08.051 · Cited by 262 · see citing works
Metabolism, Activity, and Targeting of D- and L-2-Hydroxyglutarates
Ye, D., Guan, K.-L., & Xiong, Y. (2018) · Trends in Cancer · doi:10.1016/j.trecan.2017.12.005 · Cited by 242 · see citing works
Chang, S., Yim, S., & Park, H. (2019) · Experimental & Molecular Medicine · doi:10.1038/s12276-019-0230-6 · Cited by 228 · see citing works
Metabolic reprogramming in triple-negative breast cancer
Wang, Z., Jiang, Q., & Dong, C. (2020) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2019.0210 · Cited by 248 · see citing works
Lussey-Lepoutre, C., Hollinshead, K. E. R., Ludwig, C., Menara, M., Morin, A., Castro-Vega, L.-J., Parker, S. J., Janin, M., Martinelli, C., Ottolenghi, C., et al. (2015) · Nature Communications · doi:10.1038/ncomms9784 · Cited by 227 · see citing works
Yang, Q., Liang, X., Sun, X., Zhang, L., Fu, X., Rogers, C. J., Berim, A., Zhang, S., Wang, S., Wang, B., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.08.010 · Cited by 237 · see citing works
Formate metabolism in health and disease
Pietzke, M., Meiser, J., & Vazquez, A. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2019.05.012 · Cited by 218 · see citing works
Metabolic reprogramming in triple-negative breast cancer
Sun, X., Wang, M., Wang, M., Yu, X., Guo, J., Sun, T., Li, X., Yao, L., Dong, H., & Xu, Y. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00428 · Cited by 243 · see citing works
Targeting arginine-dependent cancers with arginine-degrading enzymes: opportunities and challenges
Phillips, M. M., Sheaff, M. T., & Szlosarek, P. W. (2013) · Cancer Research and Treatment · doi:10.4143/crt.2013.45.4.251 · Cited by 229 · see citing works
Vazquez, A., Kamphorst, J. J., Markert, E. K., Schug, Z. T., Tardito, S., & Gottlieb, E. (2016) · Journal of Cell Science · doi:10.1242/jcs.181016 · Cited by 225 · see citing works
The Diverse Functions of Non-Essential Amino Acids in Cancer
Choi, B.-H., & Coloff, J. L. (2019) · Cancers · doi:10.3390/cancers11050675 · Cited by 213 · see citing works
Psat1-Dependent Fluctuations in α-Ketoglutarate Affect the Timing of ESC Differentiation
Hwang, I.-Y., Kwak, S., Lee, S., Kim, H., Lee, S. E., Kim, J.-H., Kim, Y. A., Jeon, Y. K., Chung, D. H., Jin, X., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.06.014 · Cited by 180 · see citing works
Self-citationTargeting Cancer Metabolism: Dietary and Pharmacologic Interventions
Vernieri, C., Casola, S., Foiani, M., Pietrantonio, F., de Braud, F., & Longo, V. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0615 · Cited by 202 · see citing works
Targeting Glutamine Metabolism in Breast Cancer with Aminooxyacetate
Korangath, P., Teo, W. W., Sadik, H., Han, L., Mori, N., Huijts, C. M., Wildes, F., Bharti, S., Zhang, Z., Santa-Maria, C. A., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-1200 · Cited by 182 · see citing works
Small molecule activation of PKM2 in cancer cells induces serine auxotrophy
Kung, C., Hixon, J., Choe, S., Marks, K., Gross, S., Murphy, E., DeLaBarre, B., Cianchetta, G., Sethumadhavan, S., Wang, X., et al. (2012) · Chemistry & Biology · doi:10.1016/j.chembiol.2012.07.021 · Cited by 192 · see citing works
Self-citationPetersen, A.-K., Zeilinger, S., Kastenmüller, G., Römisch-Margl, W., Brugger, M., Peters, A., Meisinger, C., Strauch, K., Hengstenberg, C., Pagel, P., et al. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddt430 · Cited by 183 · see citing works
PHGDH defines a metabolic subtype in lung adenocarcinomas with poor prognosis
Zhang, B., Zheng, A., Hydbring, P., Ambroise, G., Ouchida, A. T., Goiny, M., Vakifahmetoglu-Norberg, H., & Norberg, E. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.05.067 · Cited by 178 · see citing works
Loss of EZH2 Reprograms BCAA Metabolism to Drive Leukemic Transformation
Gu, Z., Liu, Y., Cai, F., Patrick, M., Zmajkovic, J., Cao, H., Zhang, Y., Tasdogan, A., Chen, M., Qi, L., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0152 · Cited by 173 · see citing works
Self-citationTransforming Growth Factor (TGF)-β Promotes de Novo Serine Synthesis for Collagen Production
Nigdelioglu, R., Hamanaka, R. B., Meliton, A. Y., O'Leary, E., Witt, L. J., Cho, T., Sun, K., Bonham, C., Wu, D., Woods, P. S., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.756247 · Cited by 169 · see citing works
A landscape of metabolic variation across tumor types
Reznik, E., Luna, A., Aksoy, B. A., Liu, E. M., La, K., Ostrovnaya, I., Creighton, C. J., Hakimi, A. A., & Sander, C. (2018) · Cell Systems · doi:10.1016/j.cels.2017.12.014 · Cited by 172 · see citing works
One-carbon metabolism and nucleotide biosynthesis as attractive targets for anticancer therapy
Shuvalov, O., Petukhov, A., Daks, A., Fedorova, O., Vasileva, E., & Barlev, N. A. (2017) · Oncotarget · doi:10.18632/oncotarget.15053 · Cited by 168 · see citing works
Metabolic coordination of cell fate by α-ketoglutarate-dependent dioxygenases
Baksh, S. C., & Finley, L. W. S. (2021) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.09.010 · Cited by 165 · see citing works
Diehl, F. F., Lewis, C. A., Fiske, B. P., & Vander Heiden, M. G. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0108-x · Cited by 159 · see citing works
Lu, Y., Pan, Q., Gao, W., Pu, Y., Luo, K., He, B., & Gu, Z. (2022) · Biomaterials · doi:10.1016/j.biomaterials.2021.121335 · Cited by 149 · see citing works
Wang, Q., Liberti, M. V., Liu, P., Deng, X., Liu, Y., Locasale, J. W., & Lai, L. (2017) · Cell Chemical Biology · doi:10.1016/j.chembiol.2016.11.013 · Cited by 147 · see citing works
Serine deprivation enhances antineoplastic activity of biguanides
Gravel, S.-P., Hulea, L., Toban, N., Birman, E., Blouin, M.-J., Zakikhani, M., Zhao, Y., Topisirovic, I., St-Pierre, J., & Pollak, M. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-2643-t · Cited by 138 · see citing works
Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine resistance in breast cancer
Morotti, M., Bridges, E., Valli, A., Choudhry, H., Sheldon, H., Wigfield, S., Gray, N., Zois, C. E., Grimm, F., Jones, D., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1818521116 · Cited by 131 · see citing works
2-Hydroxyglutarate in Cancer Cells
Ježek, P. (2020) · Antioxidants & Redox Signaling · doi:10.1089/ars.2019.7902 · Cited by 130 · see citing works
Extracellular serine controls epidermal stem cell fate and tumour initiation
Baksh, S. C., Todorova, P. K., Gur-Cohen, S., Hurwitz, B., Ge, Y., Novak, J. S. S., Tierney, M. T., dela Cruz-Racelis, J., Fuchs, E., & Finley, L. W. S. (2020) · Nature Cell Biology · doi:10.1038/s41556-020-0525-9 · Cited by 128 · see citing works
Reprogramming of serine, glycine and one-carbon metabolism in cancer
Li, A. M., & Ye, J. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.165841 · Cited by 127 · see citing works
Reversed argininosuccinate lyase activity in fumarate hydratase-deficient cancer cells
Zheng, L., MacKenzie, E. D., Karim, S. A., Hedley, A., Blyth, K., Kalna, G., Watson, D. G., Szlosarek, P., Frezza, C., & Gottlieb, E. (2013) · Cancer & Metabolism · doi:10.1186/2049-3002-1-12 · Cited by 103 · see citing works
Liver-Type Glutaminase GLS2 Is a Druggable Metabolic Node in Luminal-Subtype Breast Cancer
Lukey, M. J., Cluntun, A. A., Katt, W. P., Lin, M.-C. J., Druso, J. E., Ramachandran, S., Erickson, J. W., Le, H. H., Wang, Z.-E., Blank, B., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.08.076 · Cited by 103 · see citing works
Beyond the Warburg effect: How do cancer cells regulate one-carbon metabolism?
Rosenzweig, A., Blenis, J., & Gomes, A. P. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00090 · Cited by 107 · see citing works
Regulatory mechanisms of one-carbon metabolism enzymes
Petrova, B., Maynard, A. G., Wang, P., & Kanarek, N. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.105457 · Cited by 103 · see citing works
Yamaguchi, N., Weinberg, E. M., Nguyen, A., Liberti, M. V., Goodarzi, H., Janjigian, Y. Y., Paty, P. B., Saltz, L. B., Kingham, T. P., Loo, J. M., et al. (2019) · eLife · doi:10.7554/elife.52135 · Cited by 91 · see citing works
ATF3 promotes the serine synthesis pathway and tumor growth under dietary serine restriction
Li, X., Gracilla, D., Cai, L., Zhang, M., Yu, X., Chen, X., Zhang, J., Long, X., Ding, H.-F., & Yan, C. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109706 · Cited by 98 · see citing works
Wilson, J. L., Nägele, T., Linke, M., Demel, F., Fritsch, S. D., Mayr, H. K., Cai, Z., Katholnig, K., Sun, X., Fragner, L., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.01.011 · Cited by 97 · see citing works
- Authors
- 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., Chen, W. W., Barrett, F. G., Stransky, N., Tsun, Z.-Y., Cowley, G. S., Barretina, J., Kalaany, N. Y., Hsu, P. P., Ottina, K., Chan, A. M., Yuan, B., Garraway, L. A., Root, D. E., Mino-Kenudson, M., Brachtel, E. F., Driggers, E. M., & Sabatini, D. M.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- Agios Pharmaceuticals (United States) (US)
- Broad Institute (US)
- Harvard University (US)
- Corresponding author
- Sabatini, David M.
- ORCID
- Possemato, Richard
- Shaul, Yoav D.
- Pacold, Michael E.
- Kim, Dohoon
- Birsoy, Kıvanç
- Sethumadhavan, Shalini
- Jang, Hyun G.
- Jha, Abhishek K.
- Chen, Walter W.
- Barrett, Francesca G.
- Stransky, Nicolas
- Cowley, Glenn S.
- Barretina, Jordi
- Kalaany, Nada Y.
- Hsu, Peggy P.
- Yuan, Bingbing
- Garraway, Levi A.
- Root, David E.
- Mino-Kenudson, Mari
- Brachtel, Elena F.
- Sabatini, David M.
- Venue
- Nature
- Published
- 2011-08
- Volume
- 476
- Issue
- 7360
- Pages
- 346-350
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3353325
- OpenAlex
- W2022899908
- Cited by
- 1,683
- References
- 26
- Citations by year
- 2026: 72 · 2025: 111 · 2024: 120 · 2023: 116 · 2022: 138 · 2021: 167 · 2020: 137 · 2019: 126 · 2018: 93 · 2017: 97 · 2016: 125 · 2015: 93 · 2014: 109 · 2013: 72 · 2012: 87
- FWCI
- 31.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- RePEc: Research Papers in Economics (submittedVersion)
- PMC
- Funders
- Howard Hughes Medical Institute
- W. M. Keck Foundation
- Alexander and Margaret Stewart Trust
- Life Sciences Research Foundation
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- National Institutes of Health
- National Cancer Institute (CA103866, R01CA103866, R01CA129105)
- National Institute of General Medical Sciences (T32GM007753)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- PHGDH, breast cancer, cancer metabolism, breast cancer xenografts, estrogen receptor-negative breast cancer, alpha-ketoglutarate, glutamine metabolism, TCA cycle, anaplerosis, tumor metabolic reprogramming, anticancer drug targets, cell proliferation
- MeSH terms
- Animals, Breast Neoplasms, Citric Acid Cycle, Humans, Ketoglutaric Acids, Melanoma, Neoplasm Transplantation, Serine, Biomarkers, Tumor, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Glutamic Acid, Genomics, RNA Interference, Cell Line, Tumor, Cell Proliferation, Phosphoglycerate Dehydrogenase, Mice
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
