title: Autocrine TGF-β/ZEB/microRNA-200 signal transduction drives epithelial-mesenchymal transition: Kinetic models predict minimal drug dose to inhibit metastasis.
abstract: The epithelial-mesenchymal transition (EMT) is the crucial step that cancer cells must pass before they can undergo metastasis. The transition requires the activity of complex functional networks that downregulate properties of the epithelial phenotype and upregulate characteristics of the mesenchymal phenotype. The networks frequently include reciprocal repressions between transcription factors (TFs) driving the EMT and microRNAs (miRs) inducing the reverse process, termed mesenchymal-epithelial transition (MET). In this work we develop four kinetic models that are based on experimental data and hypotheses describing how autocrine transforming growth factor-β (TGF-β) signal transduction induces and maintains an EMT by upregulating the TFs ZEB1 and ZEB2 which repress the expression of the miR-200b/c family members. After successful model calibration we validate our models by predicting requirements for the maintenance of the mesenchymal steady state which agree with experimental data. Finally, we apply our validated kinetic models for the design of experiments in cancer therapy. We demonstrate how steady state properties of the kinetic models, combined with data from tumor-derived cell lines of individual patients, can predict the minimal amount of an inhibitor to induce a MET.
authors.affiliation: Department of Systems Biology and Bioinformatics, University of Rostock, 18051 Rostock, Germany; Institute for Bioinformatics, University Medicine Greifswald, 17475 Greifswald, Germany. Electronic address: katja.rateitschak@uni-greifswald.de.
authors.forename: Katja
authors.initials: K
authors.lastname: Rateitschak
authors.affiliation: Institute for Bioinformatics, University Medicine Greifswald, 17475 Greifswald, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Kaderali
authors.affiliation: Department of Systems Biology and Bioinformatics, University of Rostock, 18051 Rostock, Germany; Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Research Center at Stellenbosch University, Marais Street, Stellenbosch 7600, South Africa.
authors.forename: Olaf
authors.initials: O
authors.lastname: Wolkenhauer
authors.affiliation: Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, 18057 Rostock, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Jaster
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D052117:Benzodioxoles / Q000494:pharmacology; D003198:Computer Simulation; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D061985:Madin Darby Canine Kidney Cells; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009362:Neoplasm Metastasis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000378:metabolism
chemical_list: C519132:2-(5-benzo(1,3)dioxol-5-yl-2-tert-butyl-3H-imidazol-4-yl)-6-methylpyridine hydrochloride; D052117:Benzodioxoles; D007093:Imidazoles; D035683:MicroRNAs; D011725:Pyridines; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D000071799:Zinc Finger E-box-Binding Homeobox 1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: Design of experiments; Epithelial-mesenchymal transition; Interaction between ZEB and microRNA-200; Kinetic model; Metastasis inhibition