Regulation of metabolic pathways. A major goal of the lab is to understand how cancer cells regulate flux through metabolic pathways in order to meet the biosynthetic requirements for proliferation. We are examining three potential layers of metabolic regulation:
1. Transcriptional regulation of specific metabolic enzymes important for biomass production. In order to duplicate biomass in preparation for cell division, cancer cells must coordinate the activities of multiple metabolic pathways. The precise contributions of many of these pathways remain to be defined. We have identified candidate regulators of cancer metabolism by correlating gene expression with glycolytic flux in tumors. We are determining how these candidate regulators support biomass production and tumor growth.
2. Post-translational modification of metabolic enzymes. While transcriptional regulation results in altered levels of many metabolic enzymes in cancer, oncogenic signaling and post-translational modification provide an additional layer of regulation that allows cells to quickly respond to changes in the environment.
3. Subcellular localization of metabolic enzymes. We and others have detected pools of metabolic enzymes in several locations within the cell. We are interested in how subcellular localization of metabolic enzymes relates to flux through metabolic pathways.
Nutrient requirements to promote cell growth. We are investigating nutrient requirements and metabolic plasticity of cancer cells. There are minimal biosynthetic requirements for the cell to divide, but how cells achieve these minimal requirements is quite variable and adaptable to nutrient availability. We are using liquid chromatography followed by tandem-mass spectrometry (LC-MS/MS) to monitor nutrient consumption and production by cells under various nutrient stresses. With drugs targeting metabolic pathways entering the clinic, insight into metabolic plasticity may permit effective combination treatments.