Reliable identification of prostate cancer using mass spectrometry metabolomic imaging in needle core biopsies

Morse, Nicole Erin; Jamaspishvili, Tamara; Simon, Dávid; Patel, Palak; Ren, Kevin; Wang, Jenny; Oleschuk, Richard D.; Kaufmann, Martin; Gooding, R. J.; Berman, David M.

doi:10.1038/s41374-019-0265-2

Cited by 39 publications

(36 citation statements)

References 50 publications

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“…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.…”

Section: Resultssupporting

confidence: 85%

“…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.…”

Section: Introductionmentioning

confidence: 90%

“…This study therefore moves beyond previous cell linebased approaches to demonstrate that, despite the observed heterogeneity at the level of individual lipid species, recurrent and clinically-actionable changes in PL metabolism can be detected in tumors; some of which may represent common vulnerabilities. Lipidomic profiling of prostate tumor biopsies, possibly guided by imaging approaches as highlighted in several recent reports(16,17), has the potential to provide new information about disease features and, potentially, patient responsiveness to therapeutics such as enzalutamide.While robustly associated with sample malignancy, PL profile was only weakly linked to the most common clinicopathological characteristics of prostate cancer; PSA levels and Gleason score. While this may reflect limitations in the sample size of our cohorts, it also raises the possibility that lipidomic profiling may provide independent information regarding tumor biology and prognosis.…”

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confidence: 99%

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

Butler

Mah

Machiels

et al. 2020

Preprint

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Dysregulated lipid metabolism is a prominent feature of prostate cancer that is driven by androgen receptor (AR) signaling. Herein, we used quantitative mass spectrometry to define the "lipidome" in prostate tumors with matched benign tissues (n=21), independent tissues (n=47), and primary prostate explants cultured with a clinical AR antagonist, enzalutamide (n=43). Significant differences in lipid composition were evident and spatially visualized in tumors compared to matched benign samples. Notably, tumors featured higher proportions of monounsaturated lipids overall and elongated fatty acid chains in phosphatidylinositol and phosphatidylserine lipids. Significant associations between lipid profile and malignancy were detected, and PL composition was characteristically altered in patient tissues that responded to AR inhibition. Importantly, targeting of tumor-related lipid features, via inhibition of acetyl CoA carboxylase 1, significantly reduced cellular proliferation in tissue explants (n=13). This first characterization of the prostate cancer lipidome in clinical tissues revealed enhanced fatty acid synthesis, elongation and desaturation as tumor-defining features, with potential for therapeutic targeting.

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Section: Resultssupporting

confidence: 85%

Section: Introductionmentioning

confidence: 90%

mentioning

confidence: 99%

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

Butler

Mah

Machiels

et al. 2020

Preprint

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“…In addition, Morse et al. [ 139 ], used desorption electrospray ionization coupled to MSI (DESI-MSI) to identify metabolites with differential abundances between regions of benign and PCa tissues which also validated with pre-established metabolic pathways highlighting an importance in altered lipid metabolism in PCa. In future studies, the incorporation of patient-derived explants or xenograft models and, more recently, human PCa organoids offers the opportunity to elucidate the interactions between PCa and the tumour microenvironment in systems that more closely recapitulate the disease heterogeneity and complexity of the clinical tissue microenvironment to provide a more robust mechanistic basis by which lipid metabolism may drive PCa disease progression and treatment resistance [ 99 ].…”

Section: Conclusion and New Opportunitiesmentioning

confidence: 99%

Lipogenic effects of androgen signaling in normal and malignant prostate

Mah

Nassar

Swinnen

et al. 2020

Asian Journal of Urology

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Prostate cancer is an androgen-dependent cancer with unique metabolic features compared to many other solid tumors, and typically does not exhibit the “Warburg effect”. During malignant transformation, an early metabolic switch diverts the dependence of normal prostate cells on aerobic glycolysis for the synthesis of and secretion of citrate towards a more energetically favorable metabolic phenotype, whereby citrate is actively oxidised for energy and biosynthetic processes ( i.e. de novo lipogenesis). It is now clear that lipid metabolism is one of the key androgen-regulated processes in prostate cells and alterations in lipid metabolism are a hallmark of prostate cancer, whereby increased de novo lipogenesis accompanied by overexpression of lipid metabolic genes are characteristic of primary and advanced disease. Despite recent advances in our understanding of altered lipid metabolism in prostate tumorigenesis and cancer progression, the intermediary metabolism of the normal prostate and its relationship to androgen signaling remains poorly understood. In this review, we discuss the fundamental metabolic relationships that are distinctive in normal versus malignant prostate tissues, and the role of androgens in the regulation of lipid metabolism at different stages of prostate tumorigenesis.

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“…Molecular components associated with healthy prostatic function, such as the metabolites spermine and citrate, and the metal zinc, have long been known to have reduced levels during cancer progression [11,12], and to be associated with a worse clinical outcome [13,14]. Lower levels of citrate in prostate cancer compared to normal tissue have also been observed with MSI using desorption electrospray ionization (DESI) [15,16]. We have recently demonstrated reduced levels of citrate and aspartate, along with the metal zinc, in prostate cancer tissue using matrix-assisted laser desorption ionization (MALDI) MSI [17].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Reliable identification of prostate cancer using mass spectrometry metabolomic imaging in needle core biopsies

Cited by 39 publications

References 50 publications

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

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

Lipogenic effects of androgen signaling in normal and malignant prostate

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

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