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      Modeling cancer metabolism on a genome scale

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          Abstract

          Cancer cells have fundamentally altered cellular metabolism that is associated with their tumorigenicity and malignancy. In addition to the widely studied Warburg effect, several new key metabolic alterations in cancer have been established over the last decade, leading to the recognition that altered tumor metabolism is one of the hallmarks of cancer. Deciphering the full scope and functional implications of the dysregulated metabolism in cancer requires both the advancement of a variety of omics measurements and the advancement of computational approaches for the analysis and contextualization of the accumulated data. Encouragingly, while the metabolic network is highly interconnected and complex, it is at the same time probably the best characterized cellular network. Following, this review discusses the challenges that genome-scale modeling of cancer metabolism has been facing. We survey several recent studies demonstrating the first strides that have been done, testifying to the value of this approach in portraying a network-level view of the cancer metabolism and in identifying novel drug targets and biomarkers. Finally, we outline a few new steps that may further advance this field.

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          Most cited references120

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          On the origin of cancer cells.

          O WARBURG (1956)
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            A protocol for generating a high-quality genome-scale metabolic reconstruction.

            Network reconstructions are a common denominator in systems biology. Bottom-up metabolic network reconstructions have been developed over the last 10 years. These reconstructions represent structured knowledge bases that abstract pertinent information on the biochemical transformations taking place within specific target organisms. The conversion of a reconstruction into a mathematical format facilitates a myriad of computational biological studies, including evaluation of network content, hypothesis testing and generation, analysis of phenotypic characteristics and metabolic engineering. To date, genome-scale metabolic reconstructions for more than 30 organisms have been published and this number is expected to increase rapidly. However, these reconstructions differ in quality and coverage that may minimize their predictive potential and use as knowledge bases. Here we present a comprehensive protocol describing each step necessary to build a high-quality genome-scale metabolic reconstruction, as well as the common trials and tribulations. Therefore, this protocol provides a helpful manual for all stages of the reconstruction process.
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              Analysis of optimality in natural and perturbed metabolic networks.

              An important goal of whole-cell computational modeling is to integrate detailed biochemical information with biological intuition to produce testable predictions. Based on the premise that prokaryotes such as Escherichia coli have maximized their growth performance along evolution, flux balance analysis (FBA) predicts metabolic flux distributions at steady state by using linear programming. Corroborating earlier results, we show that recent intracellular flux data for wild-type E. coli JM101 display excellent agreement with FBA predictions. Although the assumption of optimality for a wild-type bacterium is justifiable, the same argument may not be valid for genetically engineered knockouts or other bacterial strains that were not exposed to long-term evolutionary pressure. We address this point by introducing the method of minimization of metabolic adjustment (MOMA), whereby we test the hypothesis that knockout metabolic fluxes undergo a minimal redistribution with respect to the flux configuration of the wild type. MOMA employs quadratic programming to identify a point in flux space, which is closest to the wild-type point, compatibly with the gene deletion constraint. Comparing MOMA and FBA predictions to experimental flux data for E. coli pyruvate kinase mutant PB25, we find that MOMA displays a significantly higher correlation than FBA. Our method is further supported by experimental data for E. coli knockout growth rates. It can therefore be used for predicting the behavior of perturbed metabolic networks, whose growth performance is in general suboptimal. MOMA and its possible future extensions may be useful in understanding the evolutionary optimization of metabolism.
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                Author and article information

                Journal
                Mol Syst Biol
                Mol. Syst. Biol
                msb
                Molecular Systems Biology
                John Wiley & Sons, Ltd (Chichester, UK )
                1744-4292
                1744-4292
                June 2015
                30 June 2015
                : 11
                : 6
                : 817
                Affiliations
                [1 ]The Blavatnik School of Computer Science, Tel Aviv University Tel Aviv, Israel
                [2 ]Cancer Research UK, Beatson Institute Glasgow, UK
                [3 ]The Sackler School of Medicine, Tel Aviv University Tel Aviv, Israel
                [4 ]Center for Bioinformatics and Computational Biology, University of Maryland College Park, MD, USA
                Author notes
                * Corresponding author. Tel: +972 3 640 5378; E-mail: kerenyiz@ 123456post.tau.ac.il
                ** Corresponding author. Tel: +972 3 640 6528; E-mail: ruppin@ 123456post.tau.ac.il

                Subject Categories Genome-Scale & Integrative Biology; Metabolism; Computational Biology

                Article
                10.15252/msb.20145307
                4501850
                26130389
                ea12fedb-7a9b-4433-aff9-15a123bd4402
                © 2015 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 October 2014
                : 04 April 2015
                : 26 May 2015
                Categories
                Reviews

                Quantitative & Systems biology
                cancer metabolism,metabolic modeling,genome-scale simulations

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