Tissue-specificity of cancer: linking the rewiring of molecular networks in different tissues and the mutational profiles of different cancer types

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Genetic diseases usually affect only a small subset of tissues in the human body even when the responsible genes are expressed ubiquitously. Many of these diseases impair the function of signaling pathways. Cancer, for example, interferes with the activity of cell growth- and apoptosis-related signaling pathways. These signaling pathways are not static but show different wiring and activation patterns depending on the tissue. Here, we will investigate how tissue-specific signaling contributes to the selective vulnerability of cells to disease.Signaling pathways are composed of tightly controlled cascades of protein binding events. A prerequisite to study the tissue-specific function of signaling pathways is the knowledge about which protein-protein interactions (PPIs) are realized only in a subset of all tissues. As alternative splicing and protein abundances have been shown to remodel PPI networks in a tissue-specific manner, we will use RNA sequencing and proteomics data from different human tissue to predict which previously measured PPIs are realized in which tissues. We will determine differential protein complex formation using mass spectrometry in different cell types to validate the capability of our approach to predict tissue-specific PPI networks.To use tissue-specific PPIs to predict events of tissue-specific signaling, we will additionally leverage the tissue-specific distribution of genetic variation data assuming that mutations only found in cancers originating from certain tissues are enriched in gene sets with tissue-specific functions. By solving the optimization problem of identifying subnetworks that explain the tissue-specific distribution of cancer mutations under biologically plausible constraints best, we will simultaneously reverse engineer tissue-specific pathway wiring and provide mechanistic explanations for the tissue-specific vulnerability of cells to disease mutations. We will experimentally validate our findings by demonstrating how tissue-specific pathway components can tune pathway activity and trigger cancer-related phenotypes in a tissue-specific manner.