INVESTIGATING THE HETEROGENEITY OF GLUCOSE AND GLUTAMINE METABOLISM IN CANCER

Abstract

Rapidly proliferating cancer cells have increased biosynthetic and bioenergetic needs compared to quiescent cells. Hence, they undergo a reprogramming of intermediary metabolism, mainly by upregulating the uptake and catabolism of certain nutrients. The classical example of this is the ‘Warburg effect’ or aerobic glycolysis, defined as an increase in glucose uptake coupled to lactate secretion, regardless of oxygen availability in cancer cells. One consequence of this is that the majority of glucose carbon is diverted away from the mitochondria and the tricarboxylic acid (TCA) cycle, and secreted out of the cell as lactate. This prompts some cancer cells to exhibit an increased dependence on glutamine metabolism to refill the TCA cycle. However, recent studies have uncovered widespread heterogeneity on the roles of glucose and glutamine metabolism in cancer cells, prompting a need for further clarification. In order to examine these metabolic pathways in cancer cells, I first helped develop high-resolution LC-MS metabolomic workflows. The initial objective of my thesis focused on the Warburg effect, and specifically, the increased rate of glycolytic flux that occurs in colon cancer cells. I demonstrated that changes in glycolytic flux could modify specific histone acylation marks in a dose-dependent manner, suggesting that a possible function of the Warburg effect is to confer specific signaling effects on cancer cells. The second objective of my thesis focused on defining the contribution of the mitochondrial glutaminase isoenzyme GLS2 on the observed variability in glutamine dependence in various breast cancer cell types. I identified GLS2 as an important metabolically active enzyme in breast cancer cells that can feed TCA cycle anaplerosis. This finding has important clinical implications due to the fact that a glutaminase inhibitor, which fails to block GLS2 activity, is currently in Phase II trials. In summary, my dissertation work further contributes to our fundamental understanding of the metabolic programs operating in cancer cells, by uncovering novel aspects of both glucose and glutamine metabolism. This work identifies new underlying causes of the metabolic heterogeneity observed in cancer cells and may prove relevant to future improvements in cancer therapies.