Assessment of pathological response to therapy using lipid mass spectrometry imaging

Patterson, Nathan Heath; Alabdulkarim, Balqis; Lazaris, Anthoula; Thomas, Aurélien; Marcinkiewicz, M.; Gao, Zu–Hua; Vermeulen, Peter; Chaurand, Pierre; Metrakos, Peter

doi:10.1038/srep36814

Cited by 38 publications

(23 citation statements)

References 56 publications

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“…Data were analysed with a user-independent, unbiased statistical approach, which is called unsupervised cluster analysis 23 , 24 . Tissue was segmented into regions (clusters) based on multivariate molecular patterns, which were present in the metabolomics data 25 , 26 . Segmentation of the data into 6 clusters resulted in separation of the predicted ischemic region into a separate cluster as early as 15 min of ischemia and also at all the other ischemic times (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Detecting early myocardial ischemia in rat heart by MALDI imaging mass spectrometry

Khan

Bararpour

Gorka

et al. 2021

Sci Rep

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Diagnostics of myocardial infarction in human post-mortem hearts can be achieved only if ischemia persisted for at least 6–12 h when certain morphological changes appear in myocardium. The initial 4 h of ischemia is difficult to diagnose due to lack of a standardized method. Developing a panel of molecular tissue markers is a promising approach and can be accelerated by characterization of molecular changes. This study is the first untargeted metabolomic profiling of ischemic myocardium during the initial 4 h directly from tissue section. Ischemic hearts from an ex-vivo Langendorff model were analysed using matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) at 15 min, 30 min, 1 h, 2 h, and 4 h. Region-specific molecular changes were identified even in absence of evident histological lesions and were segregated by unsupervised cluster analysis. Significantly differentially expressed features were detected by multivariate analysis starting at 15 min while their number increased with prolonged ischemia. The biggest significant increase at 15 min was observed for m/z 682.1294 (likely corresponding to S-NADHX—a damage product of nicotinamide adenine dinucleotide (NADH)). Based on the previously reported role of NAD+/NADH ratio in regulating localization of the sodium channel (Nav1.5) at the plasma membrane, Nav1.5 was evaluated by immunofluorescence. As expected, a fainter signal was observed at the plasma membrane in the predicted ischemic region starting 30 min of ischemia and the change became the most pronounced by 4 h. Metabolomic changes occur early during ischemia, can assist in identifying markers for post-mortem diagnostics and improve understanding of molecular mechanisms.

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Section: Resultsmentioning

confidence: 99%

“…Until now, MALDI IMS was used to characterize responses in diseases with evident tissue pathology (e.g. cancer and others) 5 , 26 . Our finding confirms that MALDI IMS can detect molecular perturbations even in absence of evident histological lesions (ischemic period ≤ 30 min).…”

Section: Discussionmentioning

confidence: 99%

Detecting early myocardial ischemia in rat heart by MALDI imaging mass spectrometry

Khan

Bararpour

Gorka

et al. 2021

Sci Rep

Self Cite

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“…Conversely, most of LPC inversely correlated with the resistant score. Previous studies have shown that breast and lung cancer cells are characterized by important quantitative and qualitative alterations of lipid concentrations in the plasma membrane, highlighting the ability to adapt to different environmental conditions to ensure proliferation and survival (Cifkova et al, 2015;Hilvo et al, 2011;Marien et al, 2015;Patterson et al, 2016). Moreover, lipid composition of the plasma membrane plays a critical role in the delivery of anticancer drugs to reach their intracellular targets via passive diffusion or active transport (Alves et al, 2016;Peetla et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Metabolomic profiling of pancreatic adenocarcinoma reveals fundamental clinical features

Hoare

et al. 2021

Preprint

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In this study, we perform the metabolomics profiling of 77 PDAC patient-derived tumor xenografts (PDTX) to investigate the relationship of metabolic profiles with overall survival (OS) in PDAC patients, tumor phenotypes and resistance to five anticancer drugs (gemcitabine, oxaliplatin, docetaxel, SN-38 and 5-Fluorouracil). We identified a metabolic signature that was able to predict the clinical outcome of PDAC patients (p < 0.001, HR=2.68 [95% CI: 1.5-4.9]). The correlation analysis showed that this metabolomic signature was significantly correlated with the PDAC molecular gradient (PAMG) (R = 0.44 and p < 0.001) indicating significant association to the transcriptomic phenotypes of tumors. Resistance score established, based on growth rate inhibition metrics using 35 PDTX-derived primary cells, allowed to identify several metabolites related to drug resistance which was globally accompanied by accumulation of several diacy-phospholipids and decrease in lysophospholipids. Interestingly, targeting glycerophospholipid synthesis improved sensitivity to the three tested cytotoxic drugs indicating that interfering with metabolism could be a promising therapeutic strategy to overcome the challenging resistance of PDAC.

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“…In addition, in order to determine whether the molecular distributions correlate with the cancer region in the tissue section, and to further verify if the predicted DESI MSI has greater performance in the mining of biomarker compounds, the receiver operating characteristic (ROC) curves were plotted for each raw molecular image ( Supplementary Figure 9). ROC curve is a binary classifier and have been profoundly used in evaluating test for detections of cancers over the past decades [48][49][50][51] . In our study, spatial-chemical results of the metastatic lung section obtained by DESI MSI were compared with the pathological evaluations.…”

Section: Validations Of Predicted Msimentioning

confidence: 99%

High Spatial Resolution Ambient Ionization Mass Spectrometry Imaging Using Microscopy Image Fusion Determines Tumor Margins

Lin

Chen

Huang

et al. 2019

Preprint

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Mass spectrometry imaging (MSI) using ambient ionization technique enables a direct chemical investigation of biological samples with minimal sample pretreatment. However, detailed morphological information of the sample is often lost due to its limited spatial resolution. We demonstrated that the fusion of ambient ionization MSI with optical microscopy of routine hematoxylin and eosin (H&E) staining produces predictive, high-resolution molecular imaging. In this study, desorption electrospray ionization (DESI) and nanospray desorption electrospray ionization (nanoDESI) mass spectrometry were emplo yed to visualize lipid and protein species on mouse tissue sections. The resulting molecular distributions obtained by ambient ionization MSI-microscopy fusion were verified with matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) MSI and routine immunohistochemistry (IHC) staining on the adjacent sections. Label-free molecular imaging with 5-µm spatial resolution can be achieved using DESI and nanoDESI, whereas the typical spatial resolution of ambient ionization MSI is ~100 µm. In this regard, sharpened molecular histology of tissue sections was achieved, providing complementary references to the pathology. Such multi-modality integration enabled the discovery of potential tumor biomarkers. After image fusion, we identified about 70% more potential biomarkers that could be used to determine the tumor margins on a lung tissue section with metastatic tumors. spectrometry (SIMS) MSI, were reported to achieve sharpened molecular imaging with spatial resolution at cellular level on tissue sections 36,37 . approach for image fusion was reported to be broadly applicable to different tissue type. The distribution of ions was clear at the sub-cellular level. Sharped ion images of MALDI mass spectrometry fused with microscopy of mouse tissue sections were shown in their study 37 . In addition, fusion of SIMS and electron microscopy images were also reported 38 . Although high resolution molecular distribution were revealed, these mass spectrometry methods operated under high vacuum, which limits the compatibility with conventional imaging methods for pathological examinations.In our study, an optical microscope was applied to obtain images containing meticulous details of H&E stained tissue sections. Using multivariate regression algorithm, we fused MSI with optical microscopy and generated predictive fine-grained MSI. This method was applied in different tissue types and demonstrated as a tool for cancer diagnosis. By combining optical microscopy with ambient ionization methods, DESI, and nanoDESI, for tissue mapping with image fusion, both the image resolution and image quality were greatly improved. The workflow of our study is shown in Fig. 1. ResultsElevating spatial resolution of lipid species mapping in DESI MSI. The results for fusion of DESI MSI for mouse brain and cerebellum coronal sections were shown in Fig. 2, whereas the results for mouse kidney sections were shown in Fig. 3. In Fig. 2, the dis...

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Assessment of pathological response to therapy using lipid mass spectrometry imaging

Cited by 38 publications

References 56 publications

Detecting early myocardial ischemia in rat heart by MALDI imaging mass spectrometry

Detecting early myocardial ischemia in rat heart by MALDI imaging mass spectrometry

Metabolomic profiling of pancreatic adenocarcinoma reveals fundamental clinical features

High Spatial Resolution Ambient Ionization Mass Spectrometry Imaging Using Microscopy Image Fusion Determines Tumor Margins

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