Tomer Shlomi's Lab
Departments of Computer Science and Biology,
Technion
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Our group aims to derive a comprehensive and quantitative view of cellular metabolism by combining experimental and computational tools

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. Fortunately, decades of biochemistry research produced extensive knowledge on enzymatic reactions and their assembly into metabolic networks - giving rise to a unique opportunity for quantitative analysis of a large-scale biological system.

Our research combines cellular and molecular biology, analytical chemistry, and computational approaches. Our major experimental platform is mass-spectrometry (LC/MS), enabling the detection and quantification of hundreds of metabolites per biological sample. To facilitate flux inference through specific pathways of interest, 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). This approach enables to analyze metabolic flux through networks consisting of thousands of metabolic reactions, by relying on simplified physical-chemical assumptions and optimality criteria. Our recent and ongoing research on CBM aims to augment models with complex enzyme kinetic and thermodynamic considerations, which are essential for quantitative understanding of metabolic flux.

Special interest in Cancer Metabolism

Cancer cells develop remarkably distinct metabolism compared to normal cells due to major anabolic requirements to support their abnormal proliferation. Evidence for alterations in metabolic activity in malignant cells goes back almost a century ago, where classical work on cancer bioenergetics showed enhanced glycolysis and relatively suppressed oxidative phosphorylation (a phenomenon known as the ‘Warburg effect’). Following the finding of oncogenic mutations in several metabolic enzymes, there has been a resurgence of interest in recent years on the role that metabolic alterations play in tumor development, metastasis and anticancer drug resistance.

Our research in this field has recently involved utilizing a quantitative approach to study characteristic metabolic alterations of cancer cells. For example, we quantitatively studied the causes of the Warburg effect (which remained a subject of considerable controversy since its discovery), the complex metabolism of central metabolic co-factors, ATP, NADH, and NADPH, and alterations in flux induced by oncogene activation and hypoxia. Another research focus involved the identification of synthetic lethal (SL) genes in cancer. The identification of synthetic lethality is appealing in cancers in which one of the interacting genes is somatically inactivated, as in these cases the targeting of the corresponding synthetic lethal gene is likely to selectively inhibit tumor growth, without affecting the function of healthy tissues. This involved studying synthetic lethality with the metabolic tumor suppressors, FH (fumarate hydratase) in TCA cycle, in which mutations are known to promote the formation of Hereditary Leiomyomatosis and Renal-Cell Cancer (HLRCC). Our analysis revealed novel means for selective targeting of HLRCC cells.

We are interested in the following questions: How is metabolism altered in specific cancer types? How to obtain a comprehensive and quantitative description of such alterations? 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? Can we find biomarkers that reflect specific metabolic alterations in cancer cells? How do drug resistance alter metabolism and is there a way around that?

Last updated at November, 2013