Obtaining a system level and quantitative view of cellular metabolism, studying Metabolic Systems Biology in cancer.
Achieving a system level understanding of cellular metabolism represents a major challenge from a basic science perspective, considering the complexity of the system, involving the joint activity of hundreds or thousands of biochemical reactions. Our group aims to derive a comprehensive and quantitative view of cellular metabolism by combining experimental and computational tools. Our major experimental platform is metabolomics via mass-spectrometry (LC/MS), enabling the detection and quantification of hundreds of metabolites per biological sample. To facilitate inference of metabolic flux, we employ isotope-tracing techniques and develop novel analytical approaches and algorithms for interpreting generated data. On the computational front, we further specialize in developing methods for analyzing genome-scale metabolic network models via Constraint-Based Modeling (CBM).
A special research focus of the lab is studying metabolic derangements in cancer cells. We are interested in answering the following questions: How is metabolism altered in specific cancers? Can we comprehensively quantify such metabolic changes? Are metabolic derangements tumorigenic? Or are they simply byproducts of other tumorigenic events? How are these metabolic alterations regulated? Through which signaling pathways? Are they triggered by specific genomic events? Do specific metabolic alterations in cancer cells make them vulnerable to pharmacological intervention? Does drug resistance alter metabolism and is there a way around that?
1. J. Fan, J. Ye, J. Kamphorst, T. Shlomi, C. Thompson, and J. D. Rabinowitz. Quantitative flux analysis identifies folate-dependent NADPH production. Nature (in press).
2. J. Fan, J. J. Kamphorst, J. D. Rabinowitz, T. Shlomi, Fatty acid labeling from glutamine in hypoxia can be explained by isotope exchange without net reductive IDH flux. Journal of Biological Chemistry, 288(43), 2013
3. J. Fan, J. J. Kamphorst, R. Mathew, E. White, T. Shlomi*, J. D. Rabinowitz*. (*Equal contribution) Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia. Molecular Systems Biology, 9:712, 2013.
4. T. Shlomi and J. D. Rabinowitz, Cancer metabolism mistunes methylation. Nature Chemical Biology (News and Views), 9, 2013
5. R. Adadi, B. Volkmer, R. Milo, M. Heinemann, T. Shlomi. Prediction of Microbial Growth Rate versus Biomass Yield by a Metabolic Network with Kinetic Parameters. PLoS Computational Biology, 8 (7), 2012