A Network-Based Integrative Workflow to Unravel Mechanisms Underlying Disease Progression.

Unraveling mechanisms underlying diseases has motivated the development of systems biology approaches. The key challenges for the development of mathematical models and computational tool are (1) the size of molecular networks, (2) the nonlinear nature of spatio-temporal interactions, and (3) feedback loops in the structure of interaction networks. We here propose an integrative workflow that combines structural analyses of networks, high-throughput data, and mechanistic modeling. As an illustration of the workflow, we use prostate cancer as a case study with the aim of identifying key functional components associated with primary to metastasis transitions. Analysis carried out by the workflow revealed that HOXD10, BCL2, and PGR are the most important factors affected in primary prostate samples, whereas, in the metastatic state, STAT3, JUN, and JUNB are playing a central role. The identified key elements of each network are validated using patient survival analysis. The workflow presented here allows experimentalists to use heterogeneous data sources for the identification of diagnostic and prognostic signatures.