Apocryphal FADS2 activity promotes fatty acid diversification in cancer

Young, Reuben S. E.; Bowman, Andrew P.; Williams, Elizabeth D.; Tousignant, Kaylyn D.; Bidgood, Charles L.; Narreddula, Venkateswara R.; Gupta, Rajesh; Marshall, David L.; Poad, Berwyck L. J.; Nelson, Colleen C.; Ellis, Shane R.; Heeren, Ron M. A.; Sadowski, Martin C.; Blanksby, Stephen J.

doi:10.1016/j.celrep.2021.108738

Cited by 85 publications

(135 citation statements)

References 54 publications

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“…Db-isomer distributions of the abundant monounsaturated phosphatidylcholines, PC 34:1 and PC 36:1, were investigated in rat brain tissue to assess the sensitivity and speed of the high-pressure MSI-OzID setup ( Figure 1 ). PC 34:1 and PC 36:1 have previously been studied with isomer-resolved MSI using OzID, 10 , 30 UVPD, 17 and on-tissue PB reactions, 27 which provide benchmarks for this approach. The MALDI-OzID spectrum of [PC 34:1 + Na] + ( Figure 1 A) revealed product ions indicative of two db positions, namely, n -7 ( m / z 700.45 and 716.45) and n -9 ( m / z 672.42 and 688.42).…”

Section: Resultsmentioning

confidence: 99%

Mass Spectrometry Imaging of Lipids with Isomer Resolution Using High-Pressure Ozone-Induced Dissociation

et al. 2021

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Mass spectrometry imaging (MSI) of lipids within tissues has significant potential for both biomolecular discovery and histopathological applications. Conventional MSI technologies are, however, challenged by the prevalence of phospholipid regioisomers that differ only in the location(s) of carbon–carbon double bonds and/or the relative position of fatty acyl attachment to the glycerol backbone ( i.e ., sn position). The inability to resolve isomeric lipids within imaging experiments masks underlying complexity, resulting in a critical loss of metabolic information. Herein, ozone-induced dissociation (OzID) is implemented on a mobility-enabled quadrupole time-of-flight (Q-TOF) mass spectrometer capable of matrix-assisted laser desorption/ionization (MALDI). Exploiting the ion mobility region in the Q-TOF, high number densities of ozone were accessed, leading to ∼1000-fold enhancement in the abundance of OzID product ions compared to earlier MALDI-OzID implementations. Translation of this uplift into imaging resulted in a 50-fold improvement in acquisition rate, facilitating large-area mapping with resolution of phospholipid isomers. Mapping isomer distributions across rat brain sections revealed distinct distributions of lipid isomer populations with region-specific associations of isomers differing in double bond and sn positions. Moreover, product ions arising from sequential ozone- and collision-induced dissociation enabled double bond assignments in unsaturated fatty acyl chains esterified at the noncanonical sn -1 position.

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Section: Resultsmentioning

confidence: 99%

Mass Spectrometry Imaging of Lipids with Isomer Resolution Using High-Pressure Ozone-Induced Dissociation

et al. 2021

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“…To generate the calibration ( Figure 3B ), high regiopurity PC standards ( i.e. , the sn -2 unsaturated PC 16:0/18:1 n -7 and PC 16:0/18:1 n -9) were analyzed as these sn -2 regioisomers are more commonly found in mammalian cells (typically above 90%) ( 16 ). To ensure that small contributions of the sn -1 unsaturated isomers ( i.e.…”

Section: Resultsmentioning

confidence: 99%

“…, isomers FAs 18:1 n -7 and 18:1 n -9 or isomers FAs 16:1 n -7 and 16:1 n -9). Identification and quantification of these fatty acid isomers thus presents a snapshot of cellular metabolism by providing information about lipid-enzyme interactions occurring in that location ( 16 ). Furthermore, identification of fatty acid isomers can infer molecular functions and signalling.…”

Section: Introductionmentioning

confidence: 99%

“…Mass spectrometry imaging using a MALDI-OzID modality was first demonstrated by Paine et al, who showed distinctive distributions of the phosphatidylcholine isomers PC 34:1 n -7 and PC 34:1 n -9 across murine brain tissue, revealing features that were either invisible or poorly visualized by immunochemical staining ( 29 ). Given our recent observations of distribution differences between lipid isomers across human prostate tissues ( 16 ), here we investigate the distribution of PC 34:1 double bond isomers across human prostate tumor tissue and explore correlations with the morphological tissue features determined by histopathology grading. Using a set of high purity lipid isomers (>97% regiopurity), we develop calibrations to correct for detection bias between isomers and provide relative abundance values for the lipid isomers in regions of interest.…”

Section: Introductionmentioning

confidence: 99%

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Isomer-Resolved Imaging of Prostate Cancer Tissues Reveals Specific Lipid Unsaturation Profiles Associated With Lymphocytes and Abnormal Prostate Epithelia

et al. 2021

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Prostate cancer is the fourth most common cancer worldwide with definitive diagnosis reliant on biopsy and human-graded histopathology. As with other pathologies, grading based on classical haematoxylin and eosin (H&E) staining of formalin fixed paraffin-embedded material can be prone to variation between pathologists, prompting investigation of biomolecular markers. Comprising around 50% of cellular mass, and with known metabolic variations in cancer, lipids provide a promising target for molecular pathology. Here we apply isomer-resolved lipidomics in combination with imaging mass spectrometry to interrogate tissue sections from radical prostatectomy specimens. Guided by the histopathological assessment of adjacent tissue sections, regions of interest are investigated for molecular signatures associated with lipid metabolism, especially desaturation and elongation pathways. Monitoring one of the most abundant cellular membrane lipids within these tissues, phosphatidylcholine (PC) 34:1, high positive correlation was observed between the n-9 isomer (site of unsaturation 9-carbons from the methyl terminus) and epithelial cells from potential pre-malignant lesions, while the n-7 isomer abundance was observed to correlate with immune cell infiltration and inflammation. The correlation of lipid isomer signatures with human disease states in tissue suggests a future role for isomer-resolved mass spectrometry imaging in assisting pathologists with prostate cancer diagnoses and patient stratification.

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“…Also on-tissue epoxidation [156], on-tissue ozonolysis [126], OzID [157], ion/ion reactions [158], and EID [159] have been utilized to reveal different lipid isomers and track their distributions in tissues. Most of these reports demonstrate the performance characteristics of the developed bioanalytic tools but Young et al used MALDI-OzID-MSI to show that the metabolic demand of cancer infection can alter canonical FA and GP formation, thereby creating lipids with unusual DB positions [160]. These lipid isomers and their association with breast cancer phenotypes suggest a functional role of these unsaturated lipids and showcase the power of advanced tandem MS methodologies in combination with MSI.…”

Section: Mass Spectrometry Imaging and Structure Annotationsmentioning

confidence: 99%

Advanced tandem mass spectrometry in metabolomics and lipidomics—methods and applications

Heiles

2021

Anal Bioanal Chem

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Metabolomics and lipidomics are new drivers of the omics era as molecular signatures and selected analytes allow phenotypic characterization and serve as biomarkers, respectively. The growing capabilities of untargeted and targeted workflows, which primarily rely on mass spectrometric platforms, enable extensive charting or identification of bioactive metabolites and lipids. Structural annotation of these compounds is key in order to link specific molecular entities to defined biochemical functions or phenotypes. Tandem mass spectrometry (MS), first and foremost collision-induced dissociation (CID), is the method of choice to unveil structural details of metabolites and lipids. But CID fragment ions are often not sufficient to fully characterize analytes. Therefore, recent years have seen a surge in alternative tandem MS methodologies that aim to offer full structural characterization of metabolites and lipids. In this article, principles, capabilities, drawbacks, and first applications of these “advanced tandem mass spectrometry” strategies will be critically reviewed. This includes tandem MS methods that are based on electrons, photons, and ion/molecule, as well as ion/ion reactions, combining tandem MS with concepts from optical spectroscopy and making use of derivatization strategies. In the final sections of this review, the first applications of these methodologies in combination with liquid chromatography or mass spectrometry imaging are highlighted and future perspectives for research in metabolomics and lipidomics are discussed. Graphical abstract

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Apocryphal FADS2 activity promotes fatty acid diversification in cancer

Cited by 85 publications

References 54 publications

Mass Spectrometry Imaging of Lipids with Isomer Resolution Using High-Pressure Ozone-Induced Dissociation

Mass Spectrometry Imaging of Lipids with Isomer Resolution Using High-Pressure Ozone-Induced Dissociation

Isomer-Resolved Imaging of Prostate Cancer Tissues Reveals Specific Lipid Unsaturation Profiles Associated With Lymphocytes and Abnormal Prostate Epithelia

Advanced tandem mass spectrometry in metabolomics and lipidomics—methods and applications

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