Doctor of Philosophy

dissertationThe discovery of the mitochondrial pyruvate carrier (MPC) and the ability to alter the cellular partitioning of pyruvate has allowed for exploration into the consequences for a cell with uncoupled glucose metabolism, unraveling the connections with gene expression to drive cellular proliferation and the biosynthetic requirements of cellular replication. Previous work on the MPC in cancer metabolism tested hypotheses using arguably aggressive and advanced cancer specimens, identifying a growth advantage upon MPC loss through the classic Warburg effect of uncoupled glycolysis and loss of pyruvate oxidation. Now, in the first dysplastic cells in a colon tumor, the directed study of the MPC has demonstrated the importance of metabolic compartmentation in glucose-fueled metabolic pathways in a cell's ability to regulate division autonomously. The cancer metabolism field has only recently begun to use the cell of origin's metabolism as the foundational network for the earliest metabolic aberrations in tumor initiation. In the intestinal and colon epithelium, the resident stem cells, protected at the base of the intestinal or colon crypt, give rise to intestinal and colon tumors, and thus must enact cellular programs to support dysplasia. Both in vivo and ex vivo mouse and human models have demonstrated that the MPC is again a node of regulation, with stem cells expressing lower levels of this transporter and differentiated cells expressing high levels. Interestingly, loss of the MPC throughout the crypt and across the gastrointestinal tract increased the number of tumor foci generated in two models of intestinal carcinogenesis. iv While preserving epithelial function and integrity, as well as organismal parameters of metabolism, MPC loss leading to a significant increase in tumor foci is explained by the subtle yet reproducible hyperproliferation of the stem cell niche. The pro-growth metabolic landscape thus creates a susceptibility towards dysplasia and tumorigenesis. This dissertation identified the gap in knowledge surrounding tumor initiation and addressed the question by linking the metabolic dependencies in adenocarcinoma and intestinal stem cells. The importance of the cell-autonomous approach towards cancer metabolism furthers the understanding of the complexity experienced at the tissue and organism level underlying organismal metabolic aberrations in cancer risk