Integrative Modelling of the Influence of MAPK Network on Cancer Cell Fate Decision

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.Author Summary: Depending on environmental conditions, strongly intertwined cellular signalling pathways are activated, involving activation/inactivation of proteins and genes in response to external and/or internal stimuli. Alterations of some components of these pathways can lead to wrong cell behaviours. For instance, cancer-related deregulations lead to high proliferation of malignant cells enabling sustained tumour growth. Understanding the precise mechanisms underlying these pathways is necessary to delineate efficient therapeutical approaches for each specific tumour type. We particularly focused on the Mitogen-Activated Protein Kinase (MAPK) signalling network, whose involvement in cancer is well established, although the precise conditions leading to its positive or negative influence on cell proliferation are still poorly understood. We tackled this problem by first collecting sparse published biological information into a comprehensive map describing the MAPK network in terms of stylised chemical reactions. This information source was then used to build a dynamical Boolean model recapitulating network responses to characteristic stimuli observed in selected bladder cancers. Systematic model simulations further allowed us to link specific network components and interactions with proliferative/anti-proliferative cell responses.