Isotope tracing, flux analysis and the metabolic phenotypes of transformed cells
Following decades of biochemistry research and the sequencing of the human genome, we today have a fairly comprehensive list of the enzymes available to human cells, but we still know little of how these enzymes are coordinately expressed and regulated to generate distinct metabolic phenotypes in specific cell types and conditions. Stable isotope tracing is the gold standard method for measuring metabolism in living cells, and when combined with modern mass spectrometry and computational analysis, this method holds great potential to investigate complex metabolic phenotypes of human cells and tissues in health and disease. In this talk, I will first give a brief introduction to modern isotope tracing and flux analysis, highlight some important caveats of the methodology, and then discuss the application of isotope tracing to understand cancer cell metabolism. The metabolic phenotype feature emerging from studies on cancer cells involves a curious phenomenon that might be called "wasteful" metabolism: the most well-known case is aerobic glycolysis, which degrades copious amounts of glucose into lactate which is discarded by the cell, but there is also "wasteful" metabolism of glutamine, methionine, choline, and perhaps serine. This behavior is often accompanied by metabolic dependencies (auxotrophy), where cancer cells require nutrients that are dispensable for normal cells. Moreover, cancer cells express isoforms of enzymes (isozymes) that are normally found in embryonic development, but usually absent in normal adult tissues. Some of these metabolic phenotypes are also present in activated immune cells and in pathological conditions. How these phenomena are related, and whether cancer-associated isozymes might be good targets for cancer therapeutics, are important open questions.