Integration of Global Metabolomics and Lipidomics Approaches Reveals the Molecular Mechanisms and the Potential Biomarkers for Post-Operative Recurrence in Early Stage Cholangiocarcinoma
Abstract Background: Cholangiocarcioma (CCA) is a major health problem for people in Thailand. The treatment is challenging because most of patients are diagnosed when the disease is advanced, and cancer recurrence is the main problem after treatment, leading to low survival rates. Therefore, our understanding of the mechanism underlying CCA recurrence is essential in order to prevent CCA recurrence and improve patient outcome. Methods: We performed 1H-NMR and UPLC-MS based-metabolomics on CCA serum. The differential metabolites were further analyzed using pathway analysis and potential biomarkers identification.Results: At an early stage, CCA patients with recurrence have a different metabolic profile compared with non-recurrence patients. In recurrence patients, the metabolites involved in energy metabolism, such as pyruvate metabolism and the TCA cycle, are down-regulated, while most lipids, including TGs, PCs, PEs and Pas, are up-regulated. This metabolic feature has been described in cancer stem-like cell (CSC) metabolism. Based on this, the correlation of putative CSC markers and proteins involved in identified pathways, together with recurrence-free survival was explored. The results revealed that the expression levels of the CSC markers CD44v6 and CD44v8-10 are associated with CD36 (a protein involved in lipid uptake) as well as with recurrence-free survival. Potential metabolic biomarkers were identified using ROC and Kaplan-Meier analyses. We found that citrate, sarcosine, succinate, creatine, creatinine and pyruvate and TGs have good predictive values for CCA recurrence and are associated with recurrence-free survival. Conclusions: These findings reveal an alteration of the metabolic profile associated with recurrence. These metabolic changes may be associated with the existence of CSCs that lead to CCA recurrence. Moreover, the alteration of metabolites was shown to provide suitable biomarkers for CCA recurrence. Therefore, the differential metabolites between patients with and without recurrence can be used as biomarkers for CCA recurrence.