Metabolite biomarker discovery for pancreatic neuroendocrine tumors using metabolomic approach

Abstract

Metabolic flexibility is one of the key hallmarks of cancer and metabolites are the final products of this adaptation, reflecting the tumors’ aberrant changes. However, the metabolic plasticity of pancreatic neuroendocrine tumors (pNET) is still unknown. pNETs are heterogeneous which makes their diagnosis and therapeutic management difficult. We aimed to assess the metabolomic profile of pNETs patients to understand metabolic deregulation and identify novel biomarkers. Plasma samples from 45 pNETs and 10 controls were profiled by LC−MS/MS and FIA-MS/MS targeted metabolomics analysis (Biocrates AbsoluteIDQp180kit). Explanatory multivariate statistical and unsupervised learning analysis were performed to evaluate metabolomic profiles. Finally, nonparametric comparison analysis was performed to select metabolites biomarker. As compared to controls we identified an increase of sugars, phosphatidylcholine and a decrease of carnitine levels in pNETs. An increase in phosphatidylcholine, phenylalanine, glutamine and a decrease of carnitine levels was observed for pNETs patients with MEN1 mutation as compared with MEN1 WT patients. Similarly, metastatic pNETs patients had an increased in glutamine, proline, ornithine aa, PC, glucogenic aa, spermine, putrescine and a decrease in PUFA/SFA and carnitine levels as compared to patients without metastasis. Regarding patients with pNETs G2 as compared to G1, an increase in phenylalanine, ornithine, proline aa, carnitine, sphingomyeline and spermidine was observed. For the first time, a precise comprehensive metabolic profile of pNET patients was established and different metabolic plasmatic signatures were defined depending on patient characteristics. This will be confirmed in a validation cohort currently being recruited.