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Evaluating Uncertainty in Signaling Networks Using Logical Modeling.

Kirsten Thobe1,2, Christina Kuznia3,4, Christine Sers3

  • 1Group for Discrete Biomathematics, Department for Mathematics and Computer Science, Freie Universität Berlin, Berlin, Germany.

Frontiers in Physiology
|October 27, 2018
PubMed
Summary
This summary is machine-generated.

This study introduces a new computational workflow for systems biology that integrates prior knowledge with data-driven uncertainty. The approach revealed distinct cellular wiring differences between two renal cancer cell lines, explaining their varied responses to Sorafenib.

Keywords:
constraint based modelinglogical modelingmodel checkingsignaling pathwayssystems biology

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Area of Science:

  • Systems biology
  • Computational biology
  • Cancer research

Background:

  • Traditional systems biology models struggle to incorporate prior knowledge and uncertainty.
  • Bottom-up models lack uncertainty handling, while top-down models ignore existing biological information.

Purpose of the Study:

  • To develop a novel computational workflow integrating prior knowledge and uncertainty for biological modeling.
  • To analyze differences in growth factor signaling pathways between two renal cancer cell lines with distinct Sorafenib responses.
  • To investigate the impact of Sorafenib targets, pathway crosstalk, and mTOR mutation on cellular behavior.

Main Methods:

  • Developed a workflow combining logical modeling for uncertainty with data-driven filtering.
  • Created specific templates for signaling network analysis.
  • Applied the pipeline to two renal cancer cell lines with differing Sorafenib sensitivity.
  • Analyzed uncertainties including drug targets, pathway crosstalk, and mTOR mutation.

Main Results:

  • The computational models for the two cell lines were distinct, indicating differences in cellular wiring.
  • The mutation in mammalian target of Rapamycin (mTOR) did not significantly affect its pathway activity.
  • The analysis provided insights into Sorafenib's differential effects but did not fully elucidate the mechanisms.

Conclusions:

  • The developed workflow effectively integrates prior knowledge and uncertainty in biological modeling.
  • Discrepancies in renal cancer cell line behavior towards Sorafenib are attributed to differences in cellular wiring, not mTOR mutation.
  • This approach facilitates hypothesis generation for complex biological questions in cancer research.