title: EGFR Signal-Network Reconstruction Demonstrates Metabolic Crosstalk in EMT.
abstract: Epithelial to mesenchymal transition (EMT) is an important event during development and cancer metastasis. There is limited understanding of the metabolic alterations that give rise to and take place during EMT. Dysregulation of signalling pathways that impact metabolism, including epidermal growth factor receptor (EGFR), are however a hallmark of EMT and metastasis. In this study, we report the investigation into EGFR signalling and metabolic crosstalk of EMT through constraint-based modelling and analysis of the breast epithelial EMT cell model D492 and its mesenchymal counterpart D492M. We built an EGFR signalling network for EMT based on stoichiometric coefficients and constrained the network with gene expression data to build epithelial (EGFR_E) and mesenchymal (EGFR_M) networks. Metabolic alterations arising from differential expression of EGFR genes was derived from a literature review of AKT regulated metabolic genes. Signaling flux differences between EGFR_E and EGFR_M models subsequently allowed metabolism in D492 and D492M cells to be assessed. Higher flux within AKT pathway in the D492 cells compared to D492M suggested higher glycolytic activity in D492 that we confirmed experimentally through measurements of glucose uptake and lactate secretion rates. The signaling genes from the AKT, RAS/MAPK and CaM pathways were predicted to revert D492M to D492 phenotype. Follow-up analysis of EGFR signaling metabolic crosstalk in three additional breast epithelial cell lines highlighted variability in in vitro cell models of EMT. This study shows that the metabolic phenotype may be predicted by in silico analyses of gene expression data of EGFR signaling genes, but this phenomenon is cell-specific and does not follow a simple trend.
authors.affiliation: Center for Systems Biology, University of Iceland, Reykjavik, Iceland.|Biomedical Center, University of Iceland, Reykjavik, Iceland.
authors.forename: Kumari Sonal
authors.initials: KS
authors.lastname: Choudhary
authors.affiliation: Center for Systems Biology, University of Iceland, Reykjavik, Iceland.|Biomedical Center, University of Iceland, Reykjavik, Iceland.
authors.forename: Neha
authors.initials: N
authors.lastname: Rohatgi
authors.affiliation: Center for Systems Biology, University of Iceland, Reykjavik, Iceland.|Biomedical Center, University of Iceland, Reykjavik, Iceland.
authors.forename: Skarphedinn
authors.identifier: 0000-0003-4337-9252
authors.initials: S
authors.lastname: Halldorsson
authors.affiliation: Biomedical Center, University of Iceland, Reykjavik, Iceland.|Stem Cell Research Unit, Department of Anatomy, School of Health Sciences, University of Iceland, Reykjavík, Iceland.|Department of Laboratory Hematology, Landspitali-University Hospital, Reykjavik, Iceland.
authors.forename: Eirikur
authors.initials: E
authors.lastname: Briem
authors.affiliation: Biomedical Center, University of Iceland, Reykjavik, Iceland.|Stem Cell Research Unit, Department of Anatomy, School of Health Sciences, University of Iceland, Reykjavík, Iceland.|Department of Laboratory Hematology, Landspitali-University Hospital, Reykjavik, Iceland.
authors.forename: Thorarinn
authors.initials: T
authors.lastname: Gudjonsson
authors.affiliation: Center for Systems Biology, University of Iceland, Reykjavik, Iceland.
authors.forename: Steinn
authors.initials: S
authors.lastname: Gudmundsson
authors.affiliation: Center for Systems Biology, University of Iceland, Reykjavik, Iceland.|Biomedical Center, University of Iceland, Reykjavik, Iceland.
authors.forename: Ottar
authors.initials: O
authors.lastname: Rolfsson
mesh_terms: D002460:Cell Line; D003198:Computer Simulation; D004847:Epithelial Cells / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D008954:Models, Biological; D020239:Receptor Cross-Talk / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: C512478:EGFR protein, human; D066246:ErbB Receptors