Reconstructed Metabolic Network Models Predict Flux-Level Metabolic Reprogramming in Glioblastoma

Abstract

Developments in genome scale metabolic modeling techniques and omics technologies have enabled the reconstruction of context-specific metabolic models. In this study, glioblastoma multiforme (GBM), one of the most common and aggressive malignant brain tumors, is investigated by mapping GBM gene expression data on the growth-implemented brain specific genome-scale metabolic network, and GBM-specific models are generated. The models are used to calculate metabolic flux distributions in the tumor cells. Metabolic phenotypes predicted by the GBM-specific metabolic models reconstructed in this work reflect the general metabolic reprogramming of GBM, reported both in in-vitro and in-vivo experiments. The computed flux profiles quantitatively predict that major sources of the acetyl-CoA and oxaloacetic acid pool used in TCA cycle are pyruvate dehydrogenase from glycolysis and anaplerotic flux from glutaminolysis, respectively. Also, our results, in accordance with recent studies, predict a contribution of oxidative phosphorylation to ATP pool via a slightly active TCA cycle in addition to the major contributor aerobic glycolysis. We verified our results by using different computational methods that incorporate transcriptome data with genome-scale models and by using different transcriptome datasets. Correct predictions of flux distributions in glycolysis, glutaminolysis, TCA cycle and lipid precursor metabolism validate the reconstructed models for further use in future to simulate more specific metabolic patterns for GBM.

Differential Metabolism of Medium-Chain Fatty Acids in Differentiated Human-Induced Pluripotent Stem Cell-Derived Astrocytes

“…The second step was the refinement of the transformations identified in step one based on genome scale metabolic models (i.e., astrocyte specificity) (Schultz and Cutub, 2016). In this regard, we used the astrocyte-neuronal metabolic model published by Özcan and Çakır (2016). The model provided curated astrocyte-specific metabolic information for 276 metabolites interacting across 375 reactions.…”

Genome-Scale Metabolic Modeling of Glioblastoma Reveals Promising Targets for Drug Development

“…Many of the cell's systems undergo major reprogramming as part of the tumorigenesis of GBM, some of the most significant alterations can be observed in the metabolic system (Agnihotri and Zadeh, 2016;Ozcan and Cakir, 2016). Metabolism is the collective name for the many integrated biochemical reactions in the body that are responsible for the uptake and conversion of nutrients to energy and building blocks for the cell as well as elimination of cellular waste.…”

Genome-Scale Reconstruction of the Human Astrocyte Metabolic Network

“…System approaches integrates mathematical model formulations with computational modellings, that could represent the biochemical knowledge used to strengthen experimental results (Palsson, 2009 ; Hyduke et al, 2013 ). The expression of biological phenomena using mathematical models has been used to understand how information, energy and matter behaves in the cell and to get an efficient statistical inference in experimental research by studying the dynamical behavior of cell (Najafi et al, 2014 ; Vanlier et al, 2014 ; Özcan and Çakır, 2016 ; Rajkumar et al, 2016 ).…”