Functional genomics reveals serine synthesis is essential in PHGDH-amplified breast cancer

By Richard L. Possemato, K. Marks, Yoav D. Shaul, Michael E. Pacold, Dohoon Kim, Kıvanç Birsoy, Shalini Sethumadhavan, H. Woo, H. G. Jang, Abhishek K. Jha and 17 more. Nature, 2011

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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.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/a749947a55972ce2a42e134ce2c0fc2cc687c90d

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Citations in the corpus

Links between metabolism and cancer. (2012, background): “Synthetic lethality screens aimed at metabolic enzymes uncovered an unsuspected oncogenic role for PHGDH (phosphoglycerate dehydrogenase), which catalyzes the first step in serine synthesis (Locasale et al. 2011; Possemato et al. 2011).”
One-Carbon Metabolism in Health and Disease. (2017, background): “In both breast cancer and melanoma, PHGDH is overexpressed at the protein level, due in part to genomic amplification of the locus (Locasale et al., 2011; Possemato et al., 2011).”
L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity (2016, background): “Unlike quiescent T cells, which require little nutrients and mostly use oxidative phosphorylation (OXPHOS) for their energy supply, activated T cells consume large amounts of glucose, amino acids, and fatty acids and adjust their metabolic pathways toward increased glycolytic and glutaminolytic acti”
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012, background): “One proposed function is facilitating a-ketoglutarate production for mitochondrial metabolism (Possemato et al., 2011).”
Metabolic control of cell death (2014, background): “enzymes that participate in serine-glycine metabolism promotes oncogenic transformation, an effect that depends on their catalytic activity (100, 101) In this scenario, protein kinase Cz (PKCz), which represses the activity of many of these enzymes, acts as a tumor suppressor (102).”
Metabolic heterogeneity in human lung tumors (2016, positive): “A set of 2,756 human metabolic genes (Possemato et al., 2011) was used for GSEA to define differentially expressed pathways between samples with high or low DCE signal.”