The Robust Metabolic Network Adaptations in Ultifactorial Diseases as New Targets for Novel Designed Therapies

Marta Cascante, Professor, University of Barcelona

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Launch presentation

About the speaker

Prof. Cascante is an internationally recognized expert in the field of systems biology and metabolomics, being a founder member of the systems biology and metabolomics societies and a member of the Editorial Boards of Biochemical Journal, Metabolomics, nd BMC-Systems Biology. Her specific expertise is in MFA using GC/LC-MS and computational flux modelling including software development. Prof Cascante has organised many workshops, e.g. the ESF course “Systems Biology in medicine” and has been a member of the program committee of the 2nd Metabolomics meeting in Boston (2006) and of the 7th International conference on Systems Biology (Yokohama 2006). , Significant recent publications: 1) Selivanov VA, Krause S, Roca J, Cascante M. Modeling of spatial metabolite distributions in the cardiac sarcomere. Biophys J 92, 3492-500 (2007). 2) Ramos-Montoya A, Lee WN, Bassilian S, Lim S, Trebukhina RV, Kazhyna MV, Ciudad CJ, Noe V, Centelles JJ, Cascante M. Pentose phosphate cycle oxidative and nonoxidative balance: A new vulnerable target for overcoming drug resistance in cancer. Int J Cancer 119:2733-41 (2006). 3) Selivanov VA, Marin S, Lee PW, Cascante M. Software for dynamic analysis of tracer-based metabolomic data: estimation of metabolic fluxes and their statistical analysis. Bioinformatics. 22, 2806-12 (2006). 4) Selivanov VA, Meshalkina LE, Solovjeva ON, Kuchel PW, Ramos-Montoya A, Kochetov GA, Lee PW, Cascante M. Rapid simulation and analysis of isotopomer distributions using constraints based on enzyme mechanisms: an example from HT29 cancer cells.

Abstract

Metabolic profile is the end point of the signalling events, where changes caused by diseases may be reflected. Here we present a strategy where data from incubation with 13C labelled substrates and the later isotopomer analysis of selected metabolites, are analyzed using a software developed in our laboratory to estimate dynamic flux distribution among the metabolic network. By using this strategy we have identified that maintenance of oxidative and nonoxidative pentose phosphate pathways unbalance is critical for colon cancer cell survival and vulnerable to chemotherapeutic intervention. Moreover, we identified that the specificity of phenotypic transformations in K12 and K13 mutants are related to distinct alterations in metabolic profiles which provide metabolic "fingerprints" that are correlated with different tumour phenotypes which can be exploited in multi-hit therapies. , This strategy results of great interest in imminent applications for the study of other multifactorial diseases. In particular, we are applying this strategy to achieve a better understanding of glucose metabolic network to design interventions in diabetes and COPD. This new principle for rational drug design originates from the integrative, systems biology approach of understanding cell function and opens new ways to develop novel treatments for diseases as diabetes or COPD. This work was supported by funds of Spanish Government and European Union FEDER SAF2008-00164 ISCIII-RTICC (RD06/0020/0046); European Comission (FP6) BIOBRIDGE LSHG-CT-2006-037939 and European Comission (FP7) DIAPREPP Health-F2-2008-202013; Comissió d'Universitats i Recerca de la Generalitat de Catalunya (2005SGR00204).

Launch presentation