Metabolomic profiling of pancreatic adenocarcinoma reveals fundamental clinical features

Abstract

In this study, we perform the metabolomics profiling of 77 PDAC patient-derived tumor xenografts (PDTX) to investigate the relationship of metabolic profiles with overall survival (OS) in PDAC patients, tumor phenotypes and resistance to five anticancer drugs (gemcitabine, oxaliplatin, docetaxel, SN-38 and 5-Fluorouracil). We identified a metabolic signature that was able to predict the clinical outcome of PDAC patients (p < 0.001, HR=2.68 [95% CI: 1.5-4.9]). The correlation analysis showed that this metabolomic signature was significantly correlated with the PDAC molecular gradient (PAMG) (R = 0.44 and p < 0.001) indicating significant association to the transcriptomic phenotypes of tumors. Resistance score established, based on growth rate inhibition metrics using 35 PDTX-derived primary cells, allowed to identify several metabolites related to drug resistance which was globally accompanied by accumulation of several diacy-phospholipids and decrease in lysophospholipids. Interestingly, targeting glycerophospholipid synthesis improved sensitivity to the three tested cytotoxic drugs indicating that interfering with metabolism could be a promising therapeutic strategy to overcome the challenging resistance of PDAC. Short abstractTargeting metabolism of cancer cells gives a precious opportunity to overcome challenges related to the high mortality and chemoresistance in PDAC. Metabolic profiling of PDAC patient-derived tumor xenografts used in this study allowed highlighting the strong link between metabolism and both clinical outcome of the patients and chemoresistance. Metabolic signature was able to discriminate between good and bad prognosis groups of patients based on their level of key metabolites. Identification of key metabolic markers associated to chemoresistance allowed to improve sensitivity to anticancer drugs. These results provide new insights to help to predict patient survival and elaborate new combinatory therapies against chemoresistance in PDAC patients attesting of the important clinical value of this work.