Prediction of metabolites from cancer-associated fibroblasts that control cancer cells

Abstract

Cancer-associated fibroblasts (CAFs) are a major component of tumor microenvironment (TME), and influence the progression, proliferation, and immune response of nearby cancer cells. In particular, CAFs are known to be associated with tumor metabolic reprogramming by exchanging metabolites with nearby cancer cells. To identify novel metabolites in CAFs that can control cancer cells, genome-scale metabolic models (GEM) of CAFs were reconstructed and subjected to a simulation method called flux-sum analysis, which is a metabolite-centric approach that allows identifying metabolites heavily used in each CAF. In this study, a total of five CAF GEMs were reconstructed, which were associated with breast, colon, skin, lung, or pancreatic cancers. As a control, a GEM representing a normal fibroblast from pancreas was also reconstructed. Metabolites showing greater fluxsum values in all five CAF GEMs, compared to the normal fibroblast GEM, were identified, and corresponding in vitro experiments were conducted for validation. These metabolites are expected to serve as a blueprint for analyzing the metabolism of CAFs, and also provide clues for identifying effective drug targets.