Potential Metabolite Markers for Pancreatic Cancer Identified by Metabolomic Analysis of Induced Cancer-Associated Fibroblasts

SIMPLE SUMMARY: Fibroblasts in normal tissues conduct energy metabolism via oxidative phosphorylation (OXPHOS). However, cancer-associated fibroblasts (CAFs) produce energy (i.e., ATP) via glycolysis. Nonetheless, whether intracellular metabolism transitions from OXPHOS to glycolysis when normal tissue fibroblasts differentiate into CAFs remains to be determined. Here, we established an experimental system and induced the in vitro differentiation of mesenchymal stem cells to CAFs and performed detailed metabolomic and RNA sequencing analyses. We found that the intracellular metabolic pathway was reprogrammed to the glycolytic pathway when mesenchymal stem cells were co-cultured with pancreatic cancer cells. Furthermore, we identified CAF-specific metabolites that were expressed post reprogramming. These metabolites have also been observed in pancreatic cancer mouse models, suggesting their potential as cancer biomarkers. ABSTRACT: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment perform glycolysis to produce energy, i.e., ATP. Since the origin of CAFs is unidentified, it is not determined whether the intracellular metabolism transitions from oxidative phosphorylation (OXPHOS) to glycolysis when normal tissue fibroblasts differentiate into CAFs. In this study, we established an experimental system and induced the in vitro differentiation of mesenchymal stem cells (MSCs) to CAFs. Additionally, we performed metabolomic and RNA-sequencing analyses before and after differentiation to investigate changes in the intracellular metabolism. Consequently, we discovered that OXPHOS, which was the primary intracellular metabolism in MSCs, was reprogrammed to glycolysis. Furthermore, we analyzed the metabolites in pancreatic tumor tissues in a mice model. The metabolites extracted as candidates in the in vitro experiments were also detected in the in vivo experiments. Thus, we conclude that normal tissue fibroblasts that differentiate into CAFs undergo a metabolic reprogramming from OXPHOS to glycolysis. Moreover, we identified the CAF-specific metabolites expressed during metabolic reprogramming as potential future biomarkers for pancreatic cancer.