27. UNDERSTANDING METABOLIC FUNCTION AND REGULATION IN STEM CELLS AND TUMORS

Department: Bioengineering
Faculty Advisor(s): Christian Michael Metallo

Primary Student
Name: Nathaniel Martin Vacanti
Email: nvacanti@ucsd.edu
Phone: 858-534-8209
Grad Year: 2015

Student Collaborators
Seth Parker, sjparker@ucsd.edu

Abstract
While most of the major metabolic pathways and reactions of eukaryotic cells are well characterized, many aspects of their regulation remain elusive. Metabolic pathways are highly interconnected, thus the direct regulation of one metabolite may have widespread consequences across many pathways. For this reason, it is important to study regulatory mechanisms as they act on metabolic networks, not solely on single pathways. In these studies, metabolic regulation of stem and tumor cells was examined using metabolites (tracers) labeled with stable isotope carbon atoms. The distribution of labeled carbon atoms across cellular metabolites was measured by gas chromatography/mass spectrometry and used to estimate fluxes throughout central carbon metabolism. The regulatory mechanisms of these fluxes were examined by performing these analyses under various culture conditions for stem cells and tumor cells. Human embryonic stem cells were found to utilize glutamine as a tricarboxylic acid cycle carbon source and reductive precursor to citrate in far greater amounts than differentiated cells, and the reductive flux of glutamine carbons to palmitate synthesis decreased dramatically upon induction of differentiation. Lung cancer cells lacking a functional copy of the Lkb1 tumor suppressor gene also exhibited elevated use of this pathway to produce fatty-acids under hypoxia. Tricarboxylic acid metabolism reliance shifted to glucose oxidation when a functional copy of Lkb1 was present. These results provide insights into how stem cells and tumors metabolize available nutrients, which may be useful in controlling the fate of these cells.

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