Pancreatic cancer mutationscape: revealing the link between modular restructuring and intervention efficacy amidst common mutations

Abstract

AbstractAcross cancer types, the prognosis for pancreatic cancer (PC) is among the worst and options for treatment are limited. There is increasing evidence that biological systems, including PC, are modular in both structure and function. Complex biological signaling networks such as gene regulatory networks (GRNs) are proving to be composed of subcategories that are interconnected and hierarchically ranked. These networks contain highly dynamic processes that ultimately dictate cellular function over time. In this work, we use an established Boolean multicellular signaling network of PC to show that the variance in topological rankings of the most phenotypically influential modules implies a strong relationship between structure and function. We further show that induction of mutations alters the modular structure, which analogously influences the aggression and controllability of the diseasein silico. We finally present evidence that the impact and location of mutations with respect to PC modular structure directly corresponds to the efficacy of single agent treatmentsin silico, because topologically deep mutations require deep targets for control.