Spatially resolved metabolomics to discover tumor-associated metabolic alterations

TLDR

Spatially resolved tumor metabolomics enhances understanding of cancer metabolic reprogramming and potential therapeutic targets, yet tumor heterogeneity complicates global metabolic profiling. We propose a spatially resolved metabolomics approach to identify tumor‑associated metabolites and enzymes in their native state. Using airflow‑assisted desorption electrospray ionization mass spectrometry imaging, we mapped metabolites across 256 esophageal cancer tissue samples. The approach uncovered altered metabolic pathways—including proline, glutamine, uridine, histidine, fatty acid, and polyamine biosynthesis—and six dysregulated enzymes, notably PYCR2 and UPase1, providing molecular insights into esophageal squamous cell carcinoma.

Abstract

Characterization of tumor metabolism with spatial information contributes to our understanding of complex cancer metabolic reprogramming, facilitating the discovery of potential metabolic vulnerabilities that might be targeted for tumor therapy. However, given the metabolic variability and flexibility of tumors, it is still challenging to characterize global metabolic alterations in heterogeneous cancer. Here, we propose a spatially resolved metabolomics approach to discover tumor-associated metabolites and metabolic enzymes directly in their native state. A variety of metabolites localized in different metabolic pathways were mapped by airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) in tissues from 256 esophageal cancer patients. In combination with in situ metabolomics analysis, this method provided clues into tumor-associated metabolic pathways, including proline biosynthesis, glutamine metabolism, uridine metabolism, histidine metabolism, fatty acid biosynthesis, and polyamine biosynthesis. Six abnormally expressed metabolic enzymes that are closely associated with the altered metabolic pathways were further discovered in esophageal squamous cell carcinoma (ESCC). Notably, pyrroline-5-carboxylate reductase 2 (PYCR2) and uridine phosphorylase 1 (UPase1) were found to be altered in ESCC. The spatially resolved metabolomics reveal what occurs in cancer at the molecular level, from metabolites to enzymes, and thus provide insights into the understanding of cancer metabolic reprogramming.