ABSTRACT
Disrupted regulation of cellular processes is considered one of the hallmarks of cancer. We analyze metabolomic and transcriptomic profiles jointly collected from breast cancer and hepatocellular carcinoma patients to explore the associations between the expression of metabolic enzymes and the levels of the metabolites participating in the reactions they catalyze. Surprisingly, both breast cancer and hepatocellular tumors exhibit an increase in their gene-metabolites associations compared to noncancerous adjacent tissues. Following, we build predictors of metabolite levels from the expression of the enzyme genes catalyzing them. Applying these predictors to a large cohort of breast cancer samples we find that depleted levels of key cancer-related metabolites including glucose, glycine, serine and acetate are significantly associated with improved patient survival. Thus, we show that the levels of a wide range of metabolites in breast cancer can be successfully predicted from the transcriptome, going beyond the limited set of those measured.
Subject(s)
Breast Neoplasms/genetics , Transcriptome/genetics , Carcinoma, Hepatocellular/genetics , Female , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic/genetics , Humans , Liver Neoplasms/genetics , Metabolomics/methodsABSTRACT
L-Glutamine (Gln) functions physiologically to balance the carbon and nitrogen requirements of tissues. It has been proposed that in cancer cells undergoing aerobic glycolysis, accelerated anabolism is sustained by Gln-derived carbons, which replenish the tricarboxylic acid (TCA) cycle (anaplerosis). However, it is shown here that in glioblastoma (GBM) cells, almost half of the Gln-derived glutamate (Glu) is secreted and does not enter the TCA cycle, and that inhibiting glutaminolysis does not affect cell proliferation. Moreover, Gln-starved cells are not rescued by TCA cycle replenishment. Instead, the conversion of Glu to Gln by glutamine synthetase (GS; cataplerosis) confers Gln prototrophy, and fuels de novo purine biosynthesis. In both orthotopic GBM models and in patients, (13)C-glucose tracing showed that GS produces Gln from TCA-cycle-derived carbons. Finally, the Gln required for the growth of GBM tumours is contributed only marginally by the circulation, and is mainly either autonomously synthesized by GS-positive glioma cells, or supplied by astrocytes.
Subject(s)
Brain Neoplasms/metabolism , Cell Proliferation , Glioblastoma/metabolism , Glutamate-Ammonia Ligase/metabolism , Glutamine/metabolism , Nucleotides/biosynthesis , Animals , Astrocytes/cytology , Astrocytes/metabolism , Blotting, Western , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Cell Line, Tumor , Cells, Cultured , Citric Acid Cycle , Coculture Techniques , Female , Glioblastoma/genetics , Glioblastoma/pathology , Glutamate-Ammonia Ligase/genetics , Glutamic Acid/metabolism , Humans , Male , Mice, Inbred NOD , Mice, SCID , Models, Biological , Neoplastic Stem Cells/metabolism , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Transplantation, HeterologousABSTRACT
Synthetic lethality occurs when the inhibition of two genes is lethal while the inhibition of each single gene is not. It can be harnessed to selectively treat cancer by identifying inactive genes in a given cancer and targeting their synthetic lethal (SL) partners. We present a data-driven computational pipeline for the genome-wide identification of SL interactions in cancer by analyzing large volumes of cancer genomic data. First, we show that the approach successfully captures known SL partners of tumor suppressors and oncogenes. We then validate SL predictions obtained for the tumor suppressor VHL. Next, we construct a genome-wide network of SL interactions in cancer and demonstrate its value in predicting gene essentiality and clinical prognosis. Finally, we identify synthetic lethality arising from gene overactivation and use it to predict drug efficacy. These results form a computational basis for exploiting synthetic lethality to uncover cancer-specific susceptibilities.
