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PMC12479362
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A single-cell and spatial genomics atlas of human skin fibroblasts reveals shared disease-related fibroblast subtypes across tissues.
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For prenatal skin and prenatal intestine, we concatenated raw count adata objects from intestine with our prenatal skin data from a previous publication.
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PMC12479362
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A single-cell and spatial genomics atlas of human skin fibroblasts reveals shared disease-related fibroblast subtypes across tissues.
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We ran scVI using the same parameters as for the healthy/nonlesional integration.
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PMC12479362
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A single-cell and spatial genomics atlas of human skin fibroblasts reveals shared disease-related fibroblast subtypes across tissues.
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We used the same strategy for the adult skin and prenatal skin integration.
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PMC12479362
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A single-cell and spatial genomics atlas of human skin fibroblasts reveals shared disease-related fibroblast subtypes across tissues.
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For mouse comparisons, we downloaded the mouse steady-state atlas from https://www.fibroxplorer.com/download.
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PMC12479362
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A single-cell and spatial genomics atlas of human skin fibroblasts reveals shared disease-related fibroblast subtypes across tissues.
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We loaded the data as an adata object using pandas2ri in rpy2.
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PMC12479362
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A single-cell and spatial genomics atlas of human skin fibroblasts reveals shared disease-related fibroblast subtypes across tissues.
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We used labels for Ccl19 fibroblast from the original study.
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PMC12479362
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A single-cell and spatial genomics atlas of human skin fibroblasts reveals shared disease-related fibroblast subtypes across tissues.
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Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.
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PMC12479362
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A single-cell and spatial genomics atlas of human skin fibroblasts reveals shared disease-related fibroblast subtypes across tissues.
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Any methods, additional references, Nature Portfolio reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41590-025-02267-8.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Transcriptomic studies have attempted to classify glioblastoma (GB) into subtypes that predict survival and have different therapeutic vulnerabilities.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Here we identified three metabolic subtypes: glycolytic, oxidative and a mix of glycolytic and oxidative, using mass spectrometry imaging of rapidly excised tumour sections from two patients with GB who were infused with [U-C]glucose and from spatial transcriptomic analysis of contiguous sections.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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The phenotypes are not correlated with microenvironmental features, including proliferation rate, immune cell infiltration and vascularization, are retained when patient-derived cells are grown in vitro or as orthotopically implanted xenografts and are robust to changes in oxygen concentration, demonstrating their cell-intrinsic nature.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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The spatial extent of the regions occupied by cells displaying these distinct metabolic phenotypes is large enough to be detected using clinically applicable metabolic imaging techniques.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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A limitation of the study is that it is based on only two patient tumours, albeit on multiple sections, and therefore represents a proof-of-concept study.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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GB is the most common primary adult brain cancer.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Transcriptomic analyses have attempted to classify GB into subtypes that could predict treatment response, and a recent study that used a pathway-based classification defined metabolism-associated subtypes with distinct therapeutic vulnerabilities.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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These included a mitochondrial subtype, which is associated with a more favourable clinical outcome and is sensitive to inhibitors of oxidative phosphorylation, and a glycolytic, plurimetabolic subtype that is resistant to multiple treatment types.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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An important question is the extent to which the metabolism displayed by tumour cells in vivo is cell-intrinsic and how much is defined by the tumour microenvironment (TME).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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We addressed this question by using mass spectrometry imaging (MSI) of rapidly excised tumour sections from patients with GB who were infused with [U-C]glucose immediately before surgery to image tumour cell metabolic activity in vivo and from a spatial transcriptomic analysis of adjacent sections.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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We infused three patients, two with GB and a third with an adenocarcinoma metastasis, with [U-C]glucose and performed MSI on rapidly excised tumour tissue that was dissected during tumour debulking surgery (Fig. 1a).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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We sampled 16 regions from two patients with GB and seven regions from the patient with a metastasis, the latter containing samples from normal-appearing cortex (Fig. 1b).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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There were no significant differences in lactate and glutamate C labelling between the tumour mass and tumour margin (Extended Data Fig. 1a).Fig.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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1Intra-operative freezing rapidly arrests tissue metabolism and allows visualisation of metabolic activity.a, Patients were infused intra-operatively with [U-C]glucose and underwent multi-regional tumour sampling followed by rapid freezing in liquid nitrogen (<5 s).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Tumour sections (10 μm) were analysed using DESI-MSI and MALDI-MSI, and contiguous sections were analysed by IMC.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Blood samples were collected before, during and after infusion for plasma liquid chromatography–MS (LC–MS) analysis.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Created in BioRender.com.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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b, Coronal MR images from the three patients who were infused, showing the locations of the sampled regions (blue stars).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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The number of regions sampled is shown for each patient; each region had three to six pieces of snap-frozen tissue.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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c, Plasma glucose (Glc) fractional labelling in the three infused patients.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Tumour sampling commenced at 90 min.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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d, Glucose and metabolite fractional labelling in the tumour tissue: Glc ([U-C]glucose/([U-C]glucose + [U-C]glucose) (GB1 vs GB2, P = 0.0001; GB2 vs Metastasis, P = 0.004); lactate (Lac) ([U-C]lactate/([U-C]lactate + [U-C]lactate) (GB1 vs GB2, P < 0.0001; GB2 vs Metastasis, P = 0.0002; GB1 vs Metastisis, P < 0.0001); and glutamate (Glu) ([C2]glutamate/([C2]glutamate + [U-C]glutamate) (GB1 vs GB2, P = 0.0069; GB1 vs Metastasis, P = 0.0008).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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e, ATP/ADP and PCr signal intensity ratios in each tumour section (PCr/ATP GB1 vs Metastasis, P = 0.0001; GB2 vs Metastasis, P = 0.0033).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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f, Representative tumour sections from each patient showing PCr signal intensities and ATP/ADP signal intensity ratios.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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g, Representative sections from the metastasis and from normal-appearing brain (data reproduced in three additional sections of normal cortex and nine of the metastasis); (i) Pan-cytokeratin (CK)-positive (green) adenocarcinoma cells formed tubules around a central Collagen I-positive vessel (red).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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The tubules are surrounded by vimentin-positive (pink) cortex. (
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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ii) Normal-appearing cortical tissue was obtained from the margin of the metastasis and showed vimentin-positive cells and an absence of adenocarcinoma cells.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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h, Relative abundance of [U-C]lactate (GB1 vs GB2, P < 0.0001; GB1 vs Metastasis, P = 0.0016) and [C2]glutamate (GB1 vs Metastasis, P = 0.0394) in tumour sections from GB1 (n = 22), GB2 (n = 12), the adenocarcinoma metastasis (n = 9) and normal-appearing cortex (n = 3).
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Data are means; error bars, s.d.;
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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every dot is a tissue section.
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Asterisks refer to P values obtained from a one-way ANOVA followed by Tukey’s multiple comparisons test (*P < 0.05, **P < 0.005, ***P < 0.0005, ****P < 0.00005).Source data a, Patients were infused intra-operatively with [U-C]glucose and underwent multi-regional tumour sampling followed by rapid freezing in liquid nitrogen (<5 s).
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
|
Tumour sections (10 μm) were analysed using DESI-MSI and MALDI-MSI, and contiguous sections were analysed by IMC.
|
PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
|
Blood samples were collected before, during and after infusion for plasma liquid chromatography–MS (LC–MS) analysis.
|
PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
|
Created in BioRender.com.
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
|
b, Coronal MR images from the three patients who were infused, showing the locations of the sampled regions (blue stars).
|
PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
|
The number of regions sampled is shown for each patient; each region had three to six pieces of snap-frozen tissue.
|
PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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c, Plasma glucose (Glc) fractional labelling in the three infused patients.
|
PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
|
Tumour sampling commenced at 90 min.
|
PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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d, Glucose and metabolite fractional labelling in the tumour tissue: Glc ([U-C]glucose/([U-C]glucose + [U-C]glucose) (GB1 vs GB2, P = 0.0001; GB2 vs Metastasis, P = 0.004); lactate (Lac) ([U-C]lactate/([U-C]lactate + [U-C]lactate) (GB1 vs GB2, P < 0.0001; GB2 vs Metastasis, P = 0.0002; GB1 vs Metastisis, P < 0.0001); and glutamate (Glu) ([C2]glutamate/([C2]glutamate + [U-C]glutamate) (GB1 vs GB2, P = 0.0069; GB1 vs Metastasis, P = 0.0008).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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e, ATP/ADP and PCr signal intensity ratios in each tumour section (PCr/ATP GB1 vs Metastasis, P = 0.0001; GB2 vs Metastasis, P = 0.0033).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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f, Representative tumour sections from each patient showing PCr signal intensities and ATP/ADP signal intensity ratios.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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g, Representative sections from the metastasis and from normal-appearing brain (data reproduced in three additional sections of normal cortex and nine of the metastasis); (i) Pan-cytokeratin (CK)-positive (green) adenocarcinoma cells formed tubules around a central Collagen I-positive vessel (red).
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
|
The tubules are surrounded by vimentin-positive (pink) cortex. (
|
PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
|
ii) Normal-appearing cortical tissue was obtained from the margin of the metastasis and showed vimentin-positive cells and an absence of adenocarcinoma cells.
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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h, Relative abundance of [U-C]lactate (GB1 vs GB2, P < 0.0001; GB1 vs Metastasis, P = 0.0016) and [C2]glutamate (GB1 vs Metastasis, P = 0.0394) in tumour sections from GB1 (n = 22), GB2 (n = 12), the adenocarcinoma metastasis (n = 9) and normal-appearing cortex (n = 3).
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
|
Data are means; error bars, s.d.;
|
PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
|
every dot is a tissue section.
|
PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
|
Asterisks refer to P values obtained from a one-way ANOVA followed by Tukey’s multiple comparisons test (*P < 0.05, **P < 0.005, ***P < 0.0005, ****P < 0.00005).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Source data Tissue sampling began 90 min after the start of infusion, during which time the plasma glucose fractional enrichment reached a steady state (Fig. 1c).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Fractional labelling of lactate, an end product of the glycolytic pathway, and of [C2]glutamate, which is labelled via α-ketoglutarate in the tricarboxylic acid (TCA) cycle (Extended Data Fig. 1b) in GB1 and GB2, were less than that of tumour glucose (Fig. 1d), suggesting that neither had reached isotopic steady state and were therefore a measure of glycolytic and TCA cycle activity, respectively.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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There was a direct correlation between [C2]glutamate signal intensities and the intensities of the TCA cycle intermediates [C2]malate, [C2]fumarate and [C2]succinate (Extended Data Fig. 1c).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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The signal from ceramide-1-phosphate (752.596 m/z) confirmed minimal variation in instrument performance during acquisition and uniformity of tissue preparation (Extended Data Fig. 1d).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Mass errors on the metabolite ions and the mass isotopologue distributions of all detectable labelled metabolites are given in Supplementary Tables 1 and 2, respectively.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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The sampling technique rapidly arrested tissue metabolism, as indicated by the ATP/ADP and phosphocreatine PCr/ATP ratios (Fig. 1e,f), which decline rapidly in hypoxic or ischaemic brain tissue.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Preservation of the ATP, ADP and PCr concentrations was also demonstrated using P nuclear magnetic resonance (NMR) measurements (Extended Data Fig. 2a,b).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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The metabolite C labelling observed was assumed, therefore, to be similar to that present in vivo.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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The ATP and PCr signal intensities were similar in the two GB tumours but significantly higher than those in the metastasis (Extended Data Fig. 2c).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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The concentrations of plasma amino acids and lactate did not change significantly during the infusion protocol.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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The plasma concentrations of C-labelled lactate and glutamine, although less than 10% of the unlabelled concentrations, could have contributed to some of the labelled lactate and, via glutamine, the labelled glutamate observed in the tumour sections (Extended Data Fig. 2d and Supplementary Table 3).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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The metastatic adenocarcinoma occupied small, discrete areas surrounded by gliotic and normal-appearing brain parenchyma (Fig. 1g) and therefore provided apparently normal brain tissue for comparative analysis.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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We segmented the mass spectrometry (MS) images using seven C-labelled metabolites from glycolysis ([U-C]pyruvate, [U-C]lactate) and the TCA cycle ([C2]fumarate, [C2]succinate, [C2]malate, [C2]glutamate and [C2]glutamine).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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This separated the tumour, gliotic and normal-appearing brain parenchyma and agreed with tissue classification performed by a histopathologist (Extended Data Fig. 2e).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Next, we assessed glycolytic activity and TCA cycle activity in the tumours and in normal-appearing brain.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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[U-C]lactate signals were significantly lower in GB1 than in GB2 and the metastasis, whereas the [C2]glutamate signals in GB1 were significantly higher than in the metastasis (Fig. 1h), reflecting higher glycolytic and lower TCA cycle activities in the metastasis.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Glutamate labelling in the GB tumours was comparable to that in normal brain.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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We segmented the GB MS images using the same seven C-labelled metabolites from glycolysis and the TCA cycle.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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We reasoned that the activity of these two pathways could result in four cellular states; however, the MSI spectra did not contain a high glycolytic, high TCA cycle phenotype, and images were better segmented assuming only three metabolic states (Fig. 2a and Extended Data Fig. 3a): state 3 (high glycolysis, low TCA cycle), state 2 (low glycolysis, high TCA cycle) and state 1 (low activity in both pathways).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Segmentation assuming three or four metabolic states showed that these states occupied distinct and spatially extensive regions (Fig. 2b and Extended Data Fig. 3b–e).
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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As observed previously from transcriptomic data, each tumour had a predominant metabolic phenotype, with GB1 containing more of state 2 and GB2 containing more of state 3 (Extended Data Fig. 3f).
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Nevertheless, regions occupied by one of these three metabolic states co-existed in both tumours, sometimes within a single tumour section.
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Spatial RNA sequencing of adjacent tumour sections and segmentation using Hallmark oxidative and glycolytic gene sets also found three metabolic states: glycolytic, oxidative and mixed (Extended Data Fig. 4a), which showed a strong correlation with the MSI data (Fig. 2c) and an overall concordance of 65% (Extended Data Fig. 4b).Fig.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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2Identification of metabolic phenotypes in GB tumour sections.a, Heatmap showing the average intensities of the seven metabolites used for segmentation of the three metabolic regions.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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b, Representative example of three tumour sections segmented into three clusters.
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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The region containing state 3 cells (blue) showed high [U-C]lactate and [U-C]pyruvate labelling and was considered to have a glycolytic phenotype.
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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The region containing state 2 cells (yellow) showed high labelling of [C2]glutamate and was considered to have an oxidative phenotype.
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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The region containing state 1 cells (red) showed low labelling of glycolytic and TCA cycle metabolites.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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c, Metabolic segmentation based on spatial RNA sequencing of sections contiguous with those shown in b. Blue spots correspond to a glycolytic phenotype, and yellow spots correspond to an oxidative phenotype based on Hallmark gene sets.
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Red spots correspond to cells with low glycolytic and oxidative gene signatures.
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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d, ATP/ADP and PCr/ATP signal intensity ratios (mean; error bars, s.d.)
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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in normal-appearing brain (n = 4) and in the three metabolically defined regions (region 1, n = 22; region 2, n = 14; region 3, n = 17); every dot is a unique region.
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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No statistical significance was identified using one-way ANOVA with Tukey’s multiple comparisons test.
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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e, Redox status (mean; error bars, s.d.)
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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in normal-appearing brain tissue and GB regions quantified using AsA:DHA, GSH:GSSG and [U-C]lactate/pyruvate ratios (normal brain, n = 4; region 1, n = 22; region 2, n = 14; region 3, n = 17).
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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No statistical significance was identified using one-way ANOVA with Tukey’s multiple comparisons test.
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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f, Quantification of Ki67 cells, immune cells and blood vessels (mean; error bars, s.d.)
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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in the three metabolically defined regions based on immunohistochemical analysis (region 1, n = 17; region 2, n = 4; region 3, n = 8).
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
|
No statistical significance was identified using one-way ANOVA with Tukey’s multiple comparisons test.
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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g, Spatial co-assignment of deconvolved tumour/TME signals (first row) and MSI labels (second row).
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PMC12116388
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Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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h, Violin plots showing tumour signal distribution by metabolic phenotype.
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Box plots display the median (50th percentile) as the central line, with boxes spanning the 25th and 75th percentiles.
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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Whiskers extend to the minimum and maximum values within 1.5× the interquartile range; Glyco, n = 5,440; Low, n = 8,038; Oxphos, n = 4,508.
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PMC12116388
|
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of <sup>13</sup>C-labelled glucose metabolism.
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i, Spatial uniform manifold approximation and projection (UMAP) plot of tumour-enriched spots from all metabolic phenotypes.
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