Cancer systems biology: a network modeling perspective

Abstract

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, differentiation 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 diverse genetic mutations in concert with the environmental context. 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 genomic sequencing to transcriptomic, proteomic and metabolomic profiling are now commonly used for molecular-level characterization 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 elucidate the pathways most critically involved in tumor formation and progression, impact of particular mutations on pathway operation, consequences of altered cell behavior in tissue environments and effects of molecular therapeutics.

Fig. 1.

Schematic illustration of molecular processes governing cell and tissue functional behavior, depicting how genetic alterations convolute with environmental context to yield ultimate pathos/physiological phenotypes. Environmental context influences transcriptional, translational and posttranslational processes and moreover can modulate genomic information (directly via DNA mutation or indirectly via epigenetic modulation). Thus, the molecular-level characterization containing the greatest amount of information concerning phenotypic behavior resides in the realm comprehending both genomic and environmental effects: dynamic protein network operations.