Molecular Characterization of Prostate Cancer with Associated Gleason Score Using Mass Spectrometry Imaging

Abstract

Diagnosis of prostate cancer is based on histologic evaluation of tumor architecture using a system known as the "Gleason score." This diagnostic paradigm, while the standard of care, is time-consuming, shows intraobserver variability, and provides no information about the altered metabolic pathways, which result in altered tissue architecture. Characterization of the molecular composition of prostate cancer and how it changes with respect to the Gleason score (GS) could enable a more objective and faster diagnosis. It may also aid in our understanding of disease onset and progression. In this work, we present mass spectrometry imaging for identification and mapping of lipids and metabolites in prostate tissue from patients with known prostate cancer with GS from 6 to 9. A gradient of changes in the intensity of various lipids was observed, which correlated with increasing GS. Interestingly, these changes were identified in both regions of high tumor cell density, and in regions of tissue that appeared histologically benign, possibly suggestive of precancerous metabolomic changes. A total of 31 lipids, including several phosphatidylcholines, phosphatidic acids, phosphatidylserines, phosphatidylinositols, and cardiolipins were detected with higher intensity in GS (4þ3) compared with GS (3þ4), suggesting they may be markers of prostate cancer aggression. Results obtained through mass spectrometry imaging studies were subsequently correlated with a fast, ambient mass spectrometry method for potential use as a clinical tool to support imageguided prostate biopsy. Implications: In this study, we suggest that metabolomic differences between prostate cancers with different Gleason scores can be detected by mass spectrometry imaging.

Lipidomic profiling of clinical prostate cancer reveals targetable alterations in membrane lipid composition

“…Shown in Figure 1A is a representative tumor in which comparison of spectral data from these regions revealed a tumor-specific PL composition that was distinct from that detected in pathologically benign epithelium or a region of high-grade prostatic intraepithelial neoplasia (PIN) from the same patient ( Figure 1B; Supplementary Figure 1A). Distinct PL mass spectra and specific masses (eg m/z 756.53, Figure 1A) were consistently detected in multiple independent tumor regions assessed across 3 individual PCa patients (Supplementary Figure 1B,C), consistent with recent reports (16,17) that characteristic changes in lipid composition accompany prostate tumorigenesis.…”

“…While panels of circulating plasma lipids have previously been associated with prostate cancer risk (8), diagnosis (9) and patient outcome (10), analysis of the prostate tumor lipidome has largely been confined to cell line-based studies (11)(12)(13), which lack clinical relevance. The recent evidence of malignancy-related changes in lipid composition of prostate tumors provided by mass spectrometry-based imaging studies (14)(15)(16)(17) supports undertaking a more detailed and quantitative study of the clinical prostate cancer lipidome. Moreover, treatment-related changes in the lipidome, which may reveal new resistance-related vulnerabilities, remain completely unexplored.…”

msiPL: Non-linear Manifold and Peak Learning of Mass Spectrometry Imaging Data Using Artificial Neural Networks

“…Taken together, the deep learning data analysis strategy presented here provides the ability to learn the 69 , and 3D MALDI FT-ICR MSI dataset of PDX mouse brain model of glioblastoma 3 . The MSI datasets, without prior peak picking, were exported in the standardized format imzML 49 and converted to HDF5 format 50 for variational autoencoder analysis.…”

Cardiolipin, the Mitochondrial Signature Lipid: Implication in Cancer

“…Several studies showed changes in CL content and/or composition in tumor tissues or cancer cells. In human prostate cancer tissues, changes in the quantity of various lipids including CL were observed, and CL content was found to be increased in the regions with high tumor cell density [34]. In addition, a modification of CL composition has been observed in tumor prostate tissue of patients [34].…”

“…In human prostate cancer tissues, changes in the quantity of various lipids including CL were observed, and CL content was found to be increased in the regions with high tumor cell density [34]. In addition, a modification of CL composition has been observed in tumor prostate tissue of patients [34]. Thus, in tumor tissue, CL composition in palmitoleic acid (C16:1) was increased compared with non-tumor tissue.…”