||May 7, 2015
||Atlas of Cancer Signaling Network and NaviCell: comprehensive resource and web tool for data analysis and interpretation
Studying reciprocal regulations between cancer-related pathways is essential for understanding signaling rewiring during cancer evolution and in response to treatments. With this aim we have constructed the Atlas of Cancer Signaling Network (ACSN, http://acsn.curie.fr), a resource of cancer signaling maps and tools with interactive web-based environment for navigation, curation and data visualization (http://navicell.curie.fr). The content of ACSN is represented as a seamless ‘geographic-like’ map browsable using the Google Maps engine and semantic zooming. The associated blog provides a forum for commenting and curating the ACSN maps content. The atlas contains multiple crosstalk and regulatory circuits between molecular processes implicated in cancer. The integrated NaviCell web-based tool box allows to import and visualize heterogeneous omics data on top of the ACSN maps and to perform functional analysis of the maps. NaviCell web-based tool box is also suitable for computing aggregated values for sample groups and protein families and mapping this data onto the maps. The tool contains standard heatmaps, barplots and glyphs as well as the novel map staining technique for grasping large-scale trends in numerical values projected onto a pathway map. The combination of these flexible features that provides an opportunity to adjust the modes of visualization to the data type and achieve the most meaningful picture. The NaviCell web service provides a server mode, which allows automating visualization tasks and retrieve data from maps via RESTfull (standard HTTP) calls. There is also a possibility of bindings to several programming languages as Python, R, Java.
We demonstrate how 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 also 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 interactions. To demonstrate this application of ACSN we show the study on epithelial to mesenchymal transition (EMT) signaling network from the ACSN collection has been used for finding metastasis inducers in colon cancer through network analysis. We performed structural analysis of EMT signaling network that allowed highlighting the network organization principles and complexity reduction up to core regulatory routs. Using the reduced network we modeled single and double mutants for achieving the metastasis phenotype. We predicted that a combination of p53 knock-out and overexpression of Notch would induce metastasis and suggested the molecular mechanism. This prediction lead to generation of colon cancer mice model with metastases in distant organs. We confirmed in invasive human colon cancer samples the modulation of Notch and p53 gene expression in similar manner as in the mice model, supporting a synergy between these genes to permit metastasis induction in colon.
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Chanrion M*, Kuperstein I*, Barriere C, El Marjou F, Cohen D, Vignjevic D, Stimmer L, Dos Reis Tavares S, Cacheu W, Meseure D, Fre S, Martignetti L, Paul-Gilloteaux P, Fetler L, Barillot E, Louvard D, Zinovyev A and Robine S. Concomitant Notch activation and p53 deletion trigger epithelial-to-mesenchymal transition and metastasis in mouse gut. (2014) Nature Communications, 5:5005. DOI: 10.1038/ncomms6005
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