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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.
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“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
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Metadata
- 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
- 27
- 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
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