Pan-cancer secreted proteome and skeletal muscle regulation: insight from a proteogenomic data-driven knowledge base.

Large-scale, pan-cancer analysis is enabled by data driven knowledge bases that link tumor molecular profiles with phenotypes. A debilitating cancer-related phenotype is skeletal muscle loss, or cachexia, which occurs partly from tumor products secreted into circulation. Using the LinkedOmicsKB knowledge base assembled from the Clinical Proteomics Tumor Analysis Consortium proteogenomic analysis, along with catalogs of human secretome proteins, ligand-receptor pairs and molecular signatures, we sought to identify candidate pan-cancer proteins secreted to blood that could regulate skeletal muscle phenotypes in multiple solid cancers. Tumor proteins having significant pan-cancer associations with muscle were referenced against secretome proteins secreted to blood from the Human Protein Atlas, then verified as increased in paired tumor vs. normal tissues in pan-cancer manner. This workflow revealed seven secreted proteins from cancers afflicting kidneys, head and neck, lungs and pancreas that classified as protein-binding activity modulator, extracellular matrix protein or intercellular signaling molecule. Concordance of these biomarkers with validated molecular signatures of cachexia and senescence supported relevance to muscle and cachexia disease biology, and high tumor expression of the biomarker set associated with lower overall survival. In this article, we discuss avenues by which skeletal muscle and cachexia may be regulated by these candidate pan-cancer proteins secreted to blood, and conceptualize a strategy that considers them collectively as a biomarker signature with potential for refinement by data analytics and radiogenomics for predictive testing of future risk in a non-invasive, blood-based panel amenable to broad uptake and early management.