Many human diseases are characterized by dramatic changes in metabolism, an observation that is particularly evident in cancer, where rapidly proliferating cells become highly dependent on glucose metabolism. Cancer cells, however, do not use increased levels of glycolysis to generate energy, but rather shuttle metabolic intermediates through biosynthetic pathways and rely on lactate fermentation to maintain high levels of glycolytic flux. This phenomenon, known as aerobic glycolysis or the Warburg effect, allows cancer cells to metabolize large quantities of glucose in order to generate the biomass required for cell growth and proliferation. The manner in which cancer cells rely on glucose metabolism suggests that this metabolic state could be exploited for therapeutic intervention and has become a focal point in cancer research. I have discovered that the fruit fly Drosophila melanogaster also uses aerobic glycolysis to promote growth and have established Drosophila as a model system for studying the genetic mechanisms that regulate this metabolic program. My initial efforts using this model have proven successful, as I have determined that the Drosophila Estrogen-Related Receptor (dERR) is a master regulator of aerobic glycolysis. My lab will now expand upon these initial observations to identify the molecular mechanisms that both activate and repress aerobic glycolysis in vivo. Furthermore, we have determined that Drosophila larvae use aerobic glycolysis to synthesize the oncometabolite L-2-hydroxyglutarate (L-2HG). This compound is almost exclusively studied in the context of cancer metabolism and the endogenous roles of L-2HG remain unexplored. We will determine how L-2HG synthesis is controlled in vivo and explore how this oncometabolite controls normal animal growth. Finally, we will use a combination of genetics, genomics, and metabolomics to determine how the disruption of key reactions in aerobic glycolysis affects growth and physiology. Many of these enzymes represent potential therapuetic targets and our innovative approach provides a rare opportunity to systematically evaluate the effects of inhibiting individual glycolytic enzymes in a whole animal system. Moreover, our studies also explore the compensatory metabolic pathways that are activated in response to decreased glycolytic flux, which in a clinical setting, could render tumors insenstive to drug treatments. Finally, we have uncovered an unexpected correlation between the repression of aerobic glycolysis, increased levels of fatty acid oxidation, and pyrimidine metabolism. My lab will use this unexpected discovery as a foundation to explore the poorly understood role of fatty acid beta-oxidation in nucleotide production. Our studies will allow, for the first time, a genetic dissection of the mechanisms regulating aerobic glycolysis within the context of normal animal development, and will potentially uncover novel approaches to control cellular growth at a metabolic level.

Public Health Relevance

Cancer cells use sugar metabolism as a primary means of supporting rapid growth and cell division. I have discovered that growing fruit flies (Drosophila melanogaster) use a similar form of sugar metabolism, and we are using this model genetic system to study the metabolic basis of tumor growth.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZRG1)
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Barski, Oleg
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Indiana University Bloomington
Schools of Arts and Sciences
United States
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Li, Hongde; Hurlburt, Alexander J; Tennessen, Jason M (2018) A Drosophila model of combined D-2- and L-2-hydroxyglutaric aciduria reveals a mechanism linking mitochondrial citrate export with oncometabolite accumulation. Dis Model Mech 11:
Maiuri, Ashley R; Li, Hongde; Stein, Barry D et al. (2018) Inflammation-induced DNA methylation of DNA polymerase gamma alters the metabolic profile of colon tumors. Cancer Metab 6:9
Li, Hongde; Tennessen, Jason M (2018) Preparation of Drosophila Larval Samples for Gas Chromatography-Mass Spectrometry (GC-MS)-based Metabolomics. J Vis Exp :
Krejci, Alena; Tennessen, Jason M (2017) Metabolism in time and space - exploring the frontier of developmental biology. Development 144:3193-3198
Zhang, Wenlin; Ogando, Diego G; Kim, Edward T et al. (2017) Conditionally Immortal Slc4a11-/- Mouse Corneal Endothelial Cell Line Recapitulates Disrupted Glutaminolysis Seen in Slc4a11-/- Mouse Model. Invest Ophthalmol Vis Sci 58:3723-3731
Cox, James E; Thummel, Carl S; Tennessen, Jason M (2017) Metabolomic Studies in Drosophila. Genetics 206:1169-1185
St Clair, Samantha L; Li, Hongde; Ashraf, Usman et al. (2017) Metabolomic Analysis Reveals That the Drosophila melanogaster Gene lysine Influences Diverse Aspects of Metabolism. Genetics 207:1255-1261
Li, Hongde; Chawla, Geetanjali; Hurlburt, Alexander J et al. (2017) Drosophila larvae synthesize the putative oncometabolite L-2-hydroxyglutarate during normal developmental growth. Proc Natl Acad Sci U S A 114:1353-1358
Li, Hongde; Tennessen, Jason M (2017) Methods for studying the metabolic basis of Drosophila development. Wiley Interdiscip Rev Dev Biol 6:
Zhang, Wenlin; Li, Hongde; Ogando, Diego G et al. (2017) Glutaminolysis is Essential for Energy Production and Ion Transport in Human Corneal Endothelium. EBioMedicine 16:292-301