Mesler, Arlee, 2012-2013

Arlee Mesler
Arlee
Mesler

"Alterations to Anaplerosis in Tumor Cell Metabolism by Oncogenic Kras"

Host lab: Alejandro Sweet-Cordero
Stanford University

For decades, cancer researchers have observed an increased reliance of tumor cells on glycolysis rather than the tricarboxylic acid (TCA) cycle and oxidative phosphorylation. In the context of ATP generation, this observation is counterintuitive, as glycolysis produces significantly lower ATP yields per glucose. However, recent research has indicated that this metabolic shift is beneficial for cancer cells as it shuttles carbon backbones into key anabolic pathways, helping them generate the macromolecular precursors required for rapid growth. Many nucleic acid, lipid, and protein precursors originate in the TCA cycle and are then exported out of the mitochondria to participate in biosynthetic reactions. In order for the TCA cycle to continue to function, these intermediates must be replaced. The replenishment of TCA intermediates (anaplerosis) is essential for rapidly proliferating tumor cells, although the molecular mechanisms responsible for controlling anaplerotic flux remain largely unclear. Here we are evaluating how Kras, one of the most frequently mutated oncogenes in human cancers, regulates anaplerosis in tumor cells. Given the importance of anaplerosis for tumor cells and the penetrance of Ras mutations across many different cancers, this research has broad clinical applicability.