2003, McGill University, Montreal, Canada, Experimental Medicine, Ph.D.
Signal transduction and Cancer Metabolism
Our laboratory is interested to delineate strategies used by tumor cells to survive temporary periods of nutrient deprivation and then to develop novel therapies targeting nutrient-sensing pathways of neoplastic cells. Tumor cells often display fundamental changes in metabolism and increase their uptake of nutrients to meet the increased bioenergetic demands of proliferation. Glucose and glutamine are two main nutrients whose uptake is directly controlled by signal transduction and are essential for tumor cell survival and proliferation. Altered glucose metabolism in cancer cells is termed the Warburg effect, which describes the propensity of most cancer cells to take up glucose avidly and convert it primarily to lactate, despite available oxygen. In addition to glucose, glutamine is another essential nutrient whose uptake is directly controlled by oncogenes, and it is critical for cancer cell survival and proliferation. During tumor growth, increased uptake of nutrients and rapid accumulation of cells can outstrip the supply of essential nutrients, including glucose and glutamine. How tumor cells survive these temporary periods of nutrient deprivation is unclear, but is necessary for tumorigenesis to persist. The major goal of our laboratory is to delineate the strategies, including signaling pathways, epigenetic modifications and metabolic alterations, used by tumor cells to survive periods of nutrient deprivation and then to develop novel therapies targeting nutrient-sensing pathways of neoplastic cells.
Protein Phosphatase 2A Complexes in Cancer
Reversible protein phosphorylation is the major regulatory mechanism used by cells to respond to environmental and nutritional stresses. Aberrant regulation of this activity leads to dysregulated cellular behavior and disease phenotypes, including many forms of cancer. Although we know much about how protein kinases function in specific signaling governed by phosphorylation, whether protein phosphatases are also regulated and actively function in the process to counteract kinase function has not been established. Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase that regulates many signaling pathways. Unlike kinases, serine/threonine phosphatases are promiscuously active and their specificity is governed largely by associated proteins. Thus, the specificity of PP2A is conferred by assembly of a trimeric complex including a catalytic C subunit, a scaffolding A subunit, and one of the sixteen regulatory B subunits. In addition to interacting with conventional A and B subunits, the C subunit reportedly forms two other distinct complexes with proteins designated 4 (Tap42 in yeast) and Tiprl (Tip41 in yeast). Our laboratory also interested in characterizing molecular mechanisms underlying the response of PP2A complexes to stress signals and understanding the role of PP2A regulatory subunit in cancer.