Recent studies have emphasized the importance of pathway-specific interpretations for understanding the functional relevance of gene alterations in human cancers. Although signaling activities are often conceptualized as linear events, in reality, they reflect the activity of complex functional networks assembled from modules that each respond to input signals. To acquire a deeper understanding of this network structure, we developed an approach to deconstruct pathways into modules represented by gene expression signatures. Our studies confirm that they represent units of underlying biological activity linked to known biochemical pathway structures. Importantly, we show that these signaling modules provide tools to dissect the complexity of oncogenic states that define disease outcomes as well as response to pathway-specific therapeutics. We propose that this model of pathway structure constitutes a framework to study the processes bywhich information propogates through cellular networks and to elucidate the relationships of fundamental modules to cellular and clinical phenotypes.

This paper was selected for invited commentary: see Systems Biology Makes It Personal published in Molecular Cell, April 2009

This paper was also selected for Research Highlight commentary in Nature Genetics; see A modular approach to signalling, April 2009

Research partially supported by National Science Foundation (DMS-0342172), and National Institutes of Health (NCI U54-CA-112952-01). Any opinions, findings and conclusions or recommendations expressed in this work are those of the authors and do not necessarily reflect the views of the NSF or NIH.