Identification of metabolite biomarkers for pancreatic neuroendocrine tumours using a metabolomic approach

Abstract

Importance: Metabolic flexibility, a key hallmark of cancer, reflects aberrant tumour changes associated with metabolites. The metabolic plasticity of pancreatic neuroendocrine tumours (pNETs) remains largely unexplored. Notably, the heterogeneity of pNETs complicates their diagnosis, prognosis, and therapeutic management.

Objective: Here, we compared the plasma metabolomic profiles of patients with pNET and non-cancerous individuals to understand metabolic dysregulation.

Design, setting, participants, intervention and measure: Plasma metabolic profiles of 76 patients with pNETs and 38 non-cancerous individuals were analyzed using LC-MS/MS and FIA-MS/MS (Biocrates AbsoluteIDQ p180 kit). Statistical analyses, including univariate and multivariate methods, were performed along with the generation of receiver operating characteristic (ROC) curves for metabolomic signature identification.

Results: Compared with non-cancerous individuals, patients with pNET exhibited elevated levels of phosphoglyceride metabolites and reduced acylcarnitine levels, indicating an upregulation of fatty acid oxidation (FAO), which is crucial for the energy metabolism of pNET cells and one-carbon metabolism metabolites. Elevated glutamate levels and decreased lipid metabolite levels have been observed in patients with metastatic pNETs. Patients with the germline MEN1 mutations showed lower amino acid metabolites and FAO, with increased metabolites related to leucine catabolism and lipid metabolism, compared to non-MEN1 mutated patients. The highest area under the ROC curve was observed in patients with pNET harbouring MEN1 mutations.

Conclusion and relevance: This study highlights the distinct plasma metabolic signatures of pNETs, including the critical role of FAO and elevated glutamate levels in metastasis, supporting the energy and biosynthetic needs of rapidly proliferating tumour cells. Mapping of these dysregulated metabolites may facilitate the identification of new therapeutic targets for pNETs management.

Keywords: MEN1; acylcarnitine; diagnosis biomarkers; glutathione; glycerophospholipid; metabolism; metabolomics; pNET; pancreatic neuroendocrine tumour; sphingolipid.