Spatial differentiation of metabolism in prostate cancer tissue by MALDI-TOF MSI

Abstract

Background Prostate cancer tissues are inherently heterogeneous, which presents a challenge for metabolic profiling using traditional bulk analysis methods that produce an averaged profile. The aim of this study was therefore to spatially detect metabolites and lipids on prostate tissue sections by using mass spectrometry imaging (MSI), a method that facilitates molecular imaging of heterogeneous tissue sections, which can subsequently be related to the histology of the same section. Methods Here, we simultaneously obtained metabolic and lipidomic profiles in different prostate tissue types using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MSI. Both positive and negative ion mode were applied to analyze consecutive sections from 45 fresh-frozen human prostate tissue samples (N = 15 patients). Mass identification was performed with tandem MS. Results Pairwise comparisons of cancer, non-cancer epithelium, and stroma revealed several metabolic differences between the tissue types. We detected increased levels of metabolites crucial for lipid metabolism in cancer, including metabolites involved in the carnitine shuttle, which facilitates fatty acid oxidation, and building blocks needed for lipid synthesis. Metabolites associated with healthy prostate functions, including citrate, aspartate, zinc, and spermine had lower levels in cancer compared to non-cancer epithelium. Profiling of stroma revealed higher levels of important energy metabolites, such as ADP, ATP, and glucose, and higher levels of the antioxidant taurine compared to cancer and non-cancer epithelium. Conclusions This study shows that specific tissue compartments within prostate cancer samples have distinct metabolic profiles and pinpoint the advantage of methodology providing spatial information compared to bulk analysis. We identified several differential metabolites and lipids that have potential to be developed further as diagnostic and prognostic biomarkers for prostate cancer. Spatial and rapid detection of cancer-related analytes showcases MALDI-TOF MSI as a promising and innovative diagnostic tool for the clinic.

Reproducible Lipid Alterations in Patient-Derived Breast Cancer Xenograft FFPE Tissue Identified with MALDI MSI for Pre-Clinical and Clinical Application

“…R package version 3.1-152, (accessed on 5 June 2021)). An iterative fraction-based approach of LMM was used [ 46 , 47 ]. In short, LMM testing was applied using 1% randomly selected single spectra and was repeated 100 times.…”

Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update

“…ACO2 upregulation has been identified as a key event in prostate carcinogenesis [ 113 ], a process promoted by a zinc deficiency due to the downregulation of the zinc transporter [ 115 ]. Accordingly, while the accumulation of zinc in benign prostate cells inhibits citrate oxidation and favours citrate accumulation in prostate tissue [ 113 ], lower levels of citrate, zinc, aspartate and spermine have been observed in PCa in comparison to non-cancer epithelium [ 116 , 117 ].…”

Proteomic Landscape of Prostate Cancer: The View Provided by Quantitative Proteomics, Integrative Analyses, and Protein Interactomes

“…For example, Kurreck et al [ 80 ] have performed a systematic review for MSI metabolic studies in prostate cancer for diagnostic and prognostic set-ups. Recently, MSI has been used to identify, e.g., lipids distinguishing GS (4 + 3) from GS (3 + 4) tumors [ 81 ], to find zinc and its pathway metabolites citrate and aspartate correlated with each other and showing a significant reduction in cancer compared to non-cancer epithelium [ 82 ], and to find metabolic and lipid profiles differentiating cancer, non-cancer epithelium, and stroma [ 82 ]. In addition, identification of prostate cancer from needle biopsies utilizing a multivariate metabolomic classifier based on MSI has been suggested [ 83 ].…”