Inverse system perturbations as a new methodology for identifying transcriptomic signaling participants in balanced...

We devise a novel, systems-biology approach for identifying genetic participants in homeostatic biological processes. The central idea is that genes which are inversely regulated in alignment with positive and negative system perturbation are strong candidates for significant regulatory involvement in a given homeostatic process. This allows us to integrate known genetic participants together with hitherto unknown ones into a signaling network. We illustrate this concept and justify the underlying rationale in the exemplary case of the formation of blood vessels (angiogenesis) in the progression of pancreatic cancer where we have introduced a gene regulatory network governing the shift from a non angiogenic phenotype to an angiogenic phenotype in pancreatic tissue ('angiogenic switch'). The envisaged pay-off of our approach is an improved understanding of signaling networks as well as the discovery of yet unknown genetic agents for diagnostic and therapeutic purposes. Subject to mild constraints, the same algorithm for the identification of signalling components can in principle be implemented across a wide spectrum of homeostatic processes including, e.g., apoptosis and fibrogenesis.