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Modelling signalling networks for explaining synthetic gene interactions leading to invasive phenotype in colon cancer mouse model I. Kuperstein
1

1,2,3

, D. P. A. Cohen
2

1,2,3

, L. Calzone
1,2,3
3

1,2,3

, M. Chanrion1, D. Louvard1, S.
2,3

Robine1, A. Zinovyev

and E. Barillot1,

Institut Curie, INSERM U900, Ecole des Mines ParisTech, Paris, France inna.kuperstein@curie.fr

Molecular interactions in cell create an interconnected network with multiple cross talks and regulatory loops. Understanding signalling networks rewiring in healthy cell and during disease evolution requires systems level approaches. The knowledge about cell signalling that is dispersed in thousands of publications can be systematically summarized, represented and visualized as comprehensive maps of signalling networks amenable for computational analytical methods. The rationale of construction, navigation and analysis of signalling networks is discussed and supported by an example of our project demonstrating application in research and clinics. The Atlas of Cancer Signalling Networks (ACSN, http://acsn.curie.fr and http://navicell.curie.fr) created in Institut Curie covers major mechanisms involved in cancer progression systematically represented in the form of comprehensive interconnected maps described by standardized formalism. Such signalling networks are used for visualization and analysis of high-throughput data for identifying differentially regulated areas on the signalling network for further study of mechanisms and synthetic interactions. Application of signalling networks is useful for predicting non-intuitive synthetic interactions between players in the networks. Structural analysis followed by mathematical modelling performed on signalling network enabled to predict genetic interaction. One of the examples for elucidating synthetic interactions involves construction and modelling of signalling network to predict invasive phenotype. During cancer progression, cells acquire a number of hallmarks that promote tumour growth and invasion eventually leading to metastasis. Epithelial to mesenchymal transition (EMT-like) process is considered to represent the early step in initiation of cancer invasion, and an attractive but debated concept. There are several signalling processes that govern EMT-like in cancer; these includes the major pathways


Notch, Wnt, p53, and AKT. In order to identify interplay between these signalling pathways and their impact on EMT in intestinal cells, a signalling network was manually created based on scientific literature (Fig 1A). For mathematical modelling purposes, this network was then converted and reduced into an influence network that focussed on how EMT is influenced by Notch, p53 and Wnt pathways. Logical modelling was used to formalise the hypothesis that activated Notch and p53 loss of function have synergetic effect on EMT. In addition we show a putative mechanistic model of the regulation of the transcription factors that induce EMT (Fig. 1B). Finally, as a confirmation of proposed hypothesis, in vivo mouse model with constitutively active Notch and loss of function of p53 developed highly invasive colon cancer with EMT at early stages, followed by the different stages of metastasis in distant organs; as predicted, all other single and double mouse mutants do not show EMT and lack invasive phenotype.
A

Figure 1: A). Comprehensive signalling network of Notch, p53 and Wnt pathways demonstrating regulatory loops and phenotypes B). Mechanistic model explaining EMT inducers regulation involving Notch, p53 and Wnt

1. Valastyan S. and Weinberg RA. (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147: 275-292. 2. Thiery JP et al. (2009) Epithelial mesenchymal transitions in development and disease. Cell 139: 871-890. 3. Fre S et al. (2005) Notch signals control the fate of immature progenitor cells in the intestine. Nature 435: 964-968.