Advance Access publication October 27, 2009 Cancer systems biology: a network modeling perspective

Cancer is now appreciated as not only a highly heterogenous pathology with respect to cell type and tissue origin but also as a disease involving dysregulation of multiple pathways governing fundamental cell processes such as death, proliferation, differen-tiation and migration. Thus, the activities of molecular networks that execute metabolic or cytoskeletal processes, or regulate these by signal transduction, are altered in a complex manner by di-verse genetic mutations in concert with the environmental con-text. A major challenge therefore is how to develop actionable understanding of this multivariate dysregulation, with respect both to how it arises from diverse genetic mutations and to how it may be ameliorated by prospective treatments. While high-throughput experimental platform technologies ranging from ge-nomic sequencing to transcriptomic, proteomic and metabolomic profiling are now commonly used for molecular-level character-ization of tumor cells and surrounding tissues, the resulting data sets defy straightforward intuitive interpretation with respect to potential therapeutic targets or the effects of perturbation. In this review article, we will discuss how significant advances can be obtained by applying computational modeling approaches to elu-cidate the pathways most critically involved in tumor formation and progression, impact of particular mutations on pathway op-eration, consequences of altered cell behavior in tissue environ-ments and effects of molecular therapeutics