Description of Research Expertise

Research Interests
Regulation of lymphocyte development, proliferation, survival, and transformation.

Key words: Apoptosis, carcinogenesis, immunology, signal transduction.

Description of Research
The laboratory has proposed that the basis of metazoan cell survival is determined by the inability of cells to take up nutrients in a cell-autonomous fashion. This hypothesis was formulated to explain how multicellularity might have arisen during evolution. We believe the lack of a cell intrinsic mechanism to regulate nutrient uptake provides the first and most fundamental barrier to cell transformation.

Growth Factor-Regulated Nutrient Uptake
Based on our model, we have begun to define the molecular signaling pathways that regulate nutrient uptake. Mammalian cells fuel their growth and proliferation through the catabolism of two main substrates: glucose and glutamine. Most of the remaining metabolites taken up by proliferating cells are not catabolized, but instead are utilized as building blocks during anabolic macromolecular synthesis. Non-transformed cells depend on growth factor signaling to direct glucose and glutamine uptake. These observations led us to hypothesize that there might be specific oncogenic transformation events that directly regulate the uptake and metabolism of glucose and/or glutamine. Investigations of PI3K and its downstream effects on Akt have confirmed that these oncogenes play a direct role in stimulating cellular glucose uptake and in directing the metabolic conversion to aerobic glycolysis.

Recently, we have uncovered a novel role for glutamine catabolism in cell proliferation. In addition, we now have evidence that the oncogene Myc stimulates glutamine metabolism. Furthermore, Myc-transformation addicts cells to glutamine. Exploiting this observation is under active investigation. This work underlies our successful Stand Up To Cancer (SU2C) application to investigate the role of glutamine metabolism in pancreatic cancer and develop new diagnostic and therapeutic approaches to such tumors.

Glucose Metabolism and Epigenetic Gene Control
In the last year we have begun to explore whether cellular metabolism influences nuclear events. One potential area of control would be at the level of histone modification. Histone acetylation has been implicated in influencing chromatin structure and transcription. In the last year we have provided a demonstration that the production of acetyl-CoA by ATP citrate lyase links glucose metabolism to histone modification and gene expression.

Bioenergetics and Cell Growth
Based on studying how a cell meets its synthetic and bioenergetic requirements of cell proliferation, we now have developed an active program studying the bioenergetics of cell proliferation. Growing cells require high quantities of NADPH, acetyl CoA, S-adenosyl methionine, and pentenyl pyrophosphate, all of which are direct byproducts of mitochondrial bioenergetics and can be produced only when pyruvate is in excess of that needed to produce sufficient NADH to maintain ATP production.

Much of the work summarized above is still under active investigation in the laboratory and as yet has not been reduced to publication. However, a short list of recent publications is provided below.

Rotation Projects for 2009-2010
Please contact Dr. Thompson directly about current lab rotation projects.

Lab personnel:
Tahamtan Ahmadi, M.D., Ph.D. (Postdoctoral Fellow)
Thi Bui, B.S. (Graduate Student)
Heesun Cheong, Ph.D. (Postdoctoral Fellow)
Justin Cross, Ph.D. (Postdoctoral Fellow)
Dara Ditsworth, Ph.D. (Postdoctoral Fellow)
Joshua Gruber, Ph.D. (M.D., Ph.D. Student)
Roland Knoblauch, M.D., Ph.D. (Postdoctoral Fellow)
Mei Kong, Ph.D. (Postdoctoral Fellow)
Tullia Lindsten, M.D., Ph.D. (Research Assistant Professor)
Chao Lu, B.S. (Graduate Student)
Scott Olejniczak, Ph.D. (Postdoctoral Fellow)
Uma Sachdeva, B.S. (Graduate Student)
Xuemei Tong, Ph.D. (Postdoctoral Fellow)
Patrick Ward, B.S. (Graduate Student)
Katie Wellen, Ph.D. (Postdoctoral Fellow)
Meng Welliver, M.D., Ph.D. (Postdoctoral Fellow)
David Wise, B.S. (Graduate Student)
Junmin Wu (Research Specialist)
Fangping Zhao, M.D. (Research Specialist)