Strengths and Weaknesses of Selected Modeling Methods Used in Systems Biology

Kahlem, Pascal; DiCara, Alessandro; Durot, Maxime; Hancock, John M.; Klipp, Edda; Schächter, Vincent; Segal, Eran; Xénarios, Ioannis; Birney, Ewan; Mendoza, Luis

doi:10.5772/22126

Cited by 2 publications

(2 citation statements)

References 107 publications

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“…The asynchronous behavior can be controlled by setting additional rules for time delays and priorities [ 67 , 68 ]. Alternatively, all possible transitions can be generated [ 33 , 34 , 67 , 69 ].…”

Section: Resultsmentioning

confidence: 99%

“…Computational models find their origins in engineering science, and have proved to be useful tools with which to analyze complex biological systems (for example [ 30 – 32 ]). The different types of modeling techniques can vary from qualitative Boolean models, to quantitative kinetic-based models; which of them is chosen depends on the type and amount of knowledge and experimental data available for the specific system, as well as the size of the network [ 33 , 34 ].…”

Section: Introductionmentioning

confidence: 99%

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An Extended, Boolean Model of the Septation Initiation Network in S.Pombe Provides Insights into Its Regulation

et al. 2015

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Cytokinesis in fission yeast is controlled by the Septation Initiation Network (SIN), a protein kinase signaling network using the spindle pole body as scaffold. In order to describe the qualitative behavior of the system and predict unknown mutant behaviors we decided to adopt a Boolean modeling approach. In this paper, we report the construction of an extended, Boolean model of the SIN, comprising most SIN components and regulators as individual, experimentally testable nodes. The model uses CDK activity levels as control nodes for the simulation of SIN related events in different stages of the cell cycle. The model was optimized using single knock-out experiments of known phenotypic effect as a training set, and was able to correctly predict a double knock-out test set. Moreover, the model has made in silico predictions that have been validated in vivo, providing new insights into the regulation and hierarchical organization of the SIN.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An Extended, Boolean Model of the Septation Initiation Network in S.Pombe Provides Insights into Its Regulation

et al. 2015

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Angiogenic Activity of Breast Cancer Patients’ Monocytes Reverted by Combined Use of Systems Modeling and Experimental Approaches

et al. 2015

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Angiogenesis plays a key role in tumor growth and cancer progression. TIE-2-expressing monocytes (TEM) have been reported to critically account for tumor vascularization and growth in mouse tumor experimental models, but the molecular basis of their pro-angiogenic activity are largely unknown. Moreover, differences in the pro-angiogenic activity between blood circulating and tumor infiltrated TEM in human patients has not been established to date, hindering the identification of specific targets for therapeutic intervention. In this work, we investigated these differences and the phenotypic reversal of breast tumor pro-angiogenic TEM to a weak pro-angiogenic phenotype by combining Boolean modelling and experimental approaches. Firstly, we show that in breast cancer patients the pro-angiogenic activity of TEM increased drastically from blood to tumor, suggesting that the tumor microenvironment shapes the highly pro-angiogenic phenotype of TEM. Secondly, we predicted in silico all minimal perturbations transitioning the highly pro-angiogenic phenotype of tumor TEM to the weak pro-angiogenic phenotype of blood TEM and vice versa. In silico predicted perturbations were validated experimentally using patient TEM. In addition, gene expression profiling of TEM transitioned to a weak pro-angiogenic phenotype confirmed that TEM are plastic cells and can be reverted to immunological potent monocytes. Finally, the relapse-free survival analysis showed a statistically significant difference between patients with tumors with high and low expression values for genes encoding transitioning proteins detected in silico and validated on patient TEM. In conclusion, the inferred TEM regulatory network accurately captured experimental TEM behavior and highlighted crosstalk between specific angiogenic and inflammatory signaling pathways of outstanding importance to control their pro-angiogenic activity. Results showed the successful in vitro reversion of such an activity by perturbation of in silico predicted target genes in tumor derived TEM, and indicated that targeting tumor TEM plasticity may constitute a novel valid therapeutic strategy in breast cancer.

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Strengths and Weaknesses of Selected Modeling Methods Used in Systems Biology

Cited by 2 publications

References 107 publications

An Extended, Boolean Model of the Septation Initiation Network in S.Pombe Provides Insights into Its Regulation

An Extended, Boolean Model of the Septation Initiation Network in S.Pombe Provides Insights into Its Regulation

Angiogenic Activity of Breast Cancer Patients’ Monocytes Reverted by Combined Use of Systems Modeling and Experimental Approaches

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