title: Prediction of intracellular metabolic states from extracellular metabolomic data.
abstract: Metabolic models can provide a mechanistic framework to analyze information-rich omics data sets, and are increasingly being used to investigate metabolic alternations in human diseases. An expression of the altered metabolic pathway utilization is the selection of metabolites consumed and released by cells. However, methods for the inference of intracellular metabolic states from extracellular measurements in the context of metabolic models remain underdeveloped compared to methods for other omics data. Herein, we describe a workflow for such an integrative analysis emphasizing on extracellular metabolomics data. We demonstrate, using the lymphoblastic leukemia cell lines Molt-4 and CCRF-CEM, how our methods can reveal differences in cell metabolism. Our models explain metabolite uptake and secretion by predicting a more glycolytic phenotype for the CCRF-CEM model and a more oxidative phenotype for the Molt-4 model, which was supported by our experimental data. Gene expression analysis revealed altered expression of gene products at key regulatory steps in those central metabolic pathways, and literature query emphasized the role of these genes in cancer metabolism. Moreover, in silico gene knock-outs identified unique control points for each cell line model, e.g., phosphoglycerate dehydrogenase for the Molt-4 model. Thus, our workflow is well-suited to the characterization of cellular metabolic traits based on extracellular metabolomic data, and it allows the integration of multiple omics data sets into a cohesive picture based on a defined model context.
authors.affiliation: Center for Systems Biology, University of Iceland, Reykjavik, Iceland ; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-Sur-Alzette, Luxembourg.
authors.forename: Maike K
authors.initials: MK
authors.lastname: Aurich
authors.affiliation: Center for Systems Biology, University of Iceland, Reykjavik, Iceland.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Paglia
authors.affiliation: Center for Systems Biology, University of Iceland, Reykjavik, Iceland.
authors.forename: Óttar
authors.initials: Ó
authors.lastname: Rolfsson
authors.affiliation: Center for Systems Biology, University of Iceland, Reykjavik, Iceland.
authors.forename: Sigrún
authors.initials: S
authors.lastname: Hrafnsdóttir
authors.affiliation: Center for Systems Biology, University of Iceland, Reykjavik, Iceland.
authors.forename: Manuela
authors.initials: M
authors.lastname: Magnúsdóttir
authors.affiliation: School of Health Science, Faculty of Food Science and Nutrition, University of Iceland, Reykjavik, Iceland.
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Stefaniak
authors.affiliation: Center for Systems Biology, University of Iceland, Reykjavik, Iceland ; Department of Bioengineering, University of California San Diego, La Jolla, CA USA.
authors.forename: Bernhard Ø
authors.initials: BØ
authors.lastname: Palsson
authors.affiliation: Center for Systems Biology, University of Iceland, Reykjavik, Iceland ; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-Sur-Alzette, Luxembourg.
authors.forename: Ronan M T
authors.initials: RM
authors.lastname: Fleming
authors.affiliation: Center for Systems Biology, University of Iceland, Reykjavik, Iceland ; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-Sur-Alzette, Luxembourg.
authors.forename: Ines
authors.initials: I
authors.lastname: Thiele
keywords: Constraint-based modeling; Metabolic network; Metabolomics; Multi-omics; Transcriptomics