Integrative modelling of the influence of MAPK network on cancer cell fate decision

PLoS Comput Biol. 2013 Oct;9(10):e1003286. doi: 10.1371/journal.pcbi.1003286. Epub 2013 Oct 24.

Abstract

The Mitogen-Activated Protein Kinase (MAPK) network consists of tightly interconnected signalling pathways involved in diverse cellular processes, such as cell cycle, survival, apoptosis and differentiation. Although several studies reported the involvement of these signalling cascades in cancer deregulations, the precise mechanisms underlying their influence on the balance between cell proliferation and cell death (cell fate decision) in pathological circumstances remain elusive. Based on an extensive analysis of published data, we have built a comprehensive and generic reaction map for the MAPK signalling network, using CellDesigner software. In order to explore the MAPK responses to different stimuli and better understand their contributions to cell fate decision, we have considered the most crucial components and interactions and encoded them into a logical model, using the software GINsim. Our logical model analysis particularly focuses on urinary bladder cancer, where MAPK network deregulations have often been associated with specific phenotypes. To cope with the combinatorial explosion of the number of states, we have applied novel algorithms for model reduction and for the compression of state transition graphs, both implemented into the software GINsim. The results of systematic simulations for different signal combinations and network perturbations were found globally coherent with published data. In silico experiments further enabled us to delineate the roles of specific components, cross-talks and regulatory feedbacks in cell fate decision. Finally, tentative proliferative or anti-proliferative mechanisms can be connected with established bladder cancer deregulations, namely Epidermal Growth Factor Receptor (EGFR) over-expression and Fibroblast Growth Factor Receptor 3 (FGFR3) activating mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Computational Biology / methods*
  • Computer Simulation
  • ErbB Receptors / metabolism
  • Humans
  • Intracellular Space / metabolism
  • MAP Kinase Signaling System / physiology*
  • Models, Biological*
  • Protein Interaction Maps / physiology*
  • Receptor, Fibroblast Growth Factor, Type 3 / metabolism
  • Software
  • Urinary Bladder Neoplasms / metabolism*

Substances

  • EGFR protein, human
  • ErbB Receptors
  • FGFR3 protein, human
  • Receptor, Fibroblast Growth Factor, Type 3

Grant support

The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° HEALTH-F4-2007-200767 for APO-SYS(http://cordis.europa.eu/fp7/). It has been further supported by the Agence Nationale de la Recherche, France (project MI2 iSA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.