Metabolic Reprogramming in Pheochromocytoma and Paraganglioma: Insights From Untargeted NMR Metabolomics Presurgical and Postsurgical intervention

Abstract

The aim of this study is to investigate the metabolic alterations associated with pheochromocytomas and paragangliomas (PPGLs) and the impact of surgical resection on the serum metabolome using untargeted nuclear magnetic resonance (NMR) metabolomics. For this, the study included 34 patients diagnosed with PPGLs. Pre-operative and postoperative serum samples were analyzed using 1D-proton NMR spectroscopy, and NMR spectral data were processed using Bruker software Topspin. The quantitative metabolic profiles were estimated using CHENOMX NMR-Suite, and multivariate data were analyzed using partial least squares discriminant analysis (PLS-DA) and orthogonal PLS-DA followed by random forest (RF) classification method (a machine learning approach). The multivariate analysis revealed distinct metabolic differences between pre-operative and postoperative samples with respect to normal control (NC) samples, indicating a metabolic shift following tumor resection. RF classification, with an out-of-bag error rate of 0.186, effectively distinguished between NC, presurgery, and postsurgery groups, underscoring the distinct metabolic states in PPGL and the restorative effect of surgical intervention. Pre-operative serum profiles of PPGL patients were characterized by decreased levels of key metabolites, including glucose, citrate, amino acids (glutamine, glycine, leucine, valine, tyrosine, and alanine), histidine, myo-inositol, and creatinine, suggesting altered energy metabolism, and amino acid catabolism induced by catecholamine excess. Postsurgical profiles showed partial metabolic restoration, with significant increases in proline, glutamate, and 3-hydroxybutyrate (3-HB) (p < 0.01), indicating normalization involving lipid oxidation and amino acid metabolism. Although plasma metanephrines normalized postsurgery, full biochemical recovery lagged, as metabolic profiles of postoperative patients remained distinct from healthy controls. In conclusion, the present untargeted NMR metabolomics revealed significant metabolic reprogramming in PPGL patients and captured the partial normalization of metabolic pathways following tumor resection. Metabolites such as proline, glutamate, and 3-HB emerged as potential biomarkers of treatment response. These findings underscore the utility of metabolomics to identify biomarkers for monitoring disease progression, assessing postsurgical recovery, and improving our understanding of PPGL pathophysiology.

Keywords: NMR based metabolomics; metabolic signatures; neuroendocrine tumors; paraganglioma; pheochromocytoma.