title: S100A4 and its role in metastasis – computational integration of data on biological networks.
abstract: Characterising signal transduction networks is fundamental to our understanding of biology. However, redundancy and different types of feedback mechanisms make it difficult to understand how variations of the network components contribute to a biological process. In silico modelling of signalling interactions therefore becomes increasingly useful for the development of successful therapeutic approaches. Unfortunately, quantitative information cannot be obtained for all of the proteins or complexes that comprise the network, which limits the usability of computational models. We developed a flexible computational framework for the analysis of biological signalling networks. We demonstrate our approach by studying the mechanism of metastasis promotion by the S100A4 protein, and suggest therapeutic strategies. The advantage of the proposed method is that only limited information (interaction type between species) is required to set up a steady-state network model. This permits a straightforward integration of experimental information where the lack of details are compensated by efficient sampling of the parameter space. We investigated regulatory properties of the S100A4 network and the role of different key components. The results show that S100A4 enhances the activity of matrix metalloproteinases (MMPs), causing higher cell dissociation. Moreover, it leads to an increased stability of the pathological state. Thus, avoiding metastasis in S100A4-expressing tumours requires multiple target inhibition. Moreover, the analysis could explain the previous failure of MMP inhibitors in clinical trials. Finally, our method is applicable to a wide range of biological questions that can be represented as directional networks.
authors.affiliation: Department of Chemistry and Biomedical Sciences, Linnæus University, Kalmar, Sweden. antoine.buetti@lnu.se ran.friedman@lnu.se.
authors.forename: Antoine
authors.initials: A
authors.lastname: Buetti-Dinh
authors.forename: Igor V
authors.initials: IV
authors.lastname: Pivkin
authors.forename: Ran
authors.initials: R
authors.lastname: Friedman
mesh_terms: D019295:Computational Biology / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics*; D015398:Signal Transduction; D049490:Systems Biology
chemical_list: D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C077591:S100A4 protein, human; D020782:Matrix Metalloproteinases