Single-cell characterization of macrophages in glioblastoma reveals MARCO as a mesenchymal pro-tumor marker
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA593249 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10582353_1.fastq.gz | Fastqsanger.gz | |||
| SRR10582353_2.fastq.gz | Fastqsanger.gz | |||
| SRR10582354_1.fastq.gz | Fastqsanger.gz | |||
| SRR10582354_2.fastq.gz | Fastqsanger.gz | |||
| SRR10582355_1.fastq.gz | Fastqsanger.gz |
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Project description:Macrophages are the most common infiltrating immune cells in glioblastoma (GBM), and play a wide variety of pro-tumor and anti-tumor roles. However, the different subpopulations of macrophages and their effects on the tumor microenvironment remain poorly understood. Here, we combine new and previously-published single-cell RNA-seq data from 86,279 single cells from a total of 63 gliomas to profile 17,774 individual macrophages. Unsupervised clustering revealed an anti-inflammatory subpopulation of macrophages characterized by expression of MARCO (macrophage receptor with collagenous structure), a gene which has not been previously well-characterized in gliomas. MARCO is almost exclusively expressed in macrophages of IDH1-wildtype GBM rather than IDH1-mutated GBM or lower-grade gliomas. Previous studies have implicated MARCO as an unfavorable marker in melanoma and non-small-cell lung cancer; here, we find that bulk MARCO expression is associated with worse prognosis in TCGA glioblastomas, and associates with the mesenchymal expression subtype. Our single-cell analysis shows that this previously-reported mesenchymal signature primarily arises from MARCO-expressing macrophages. These MARCO-expressing macrophages differentially over-express gene sets related to hypoxia and the epithelial-mesenchymal transition, and under-express gene sets related to inflammation and antigen presentation. We show evidence that MARCO-expressing macrophages are recruited from the blood (as opposed to being resident microglia), and paired single-cell analysis of tumor and myeloid cells demonstrate that this recruitment may be driven by known chemoattractant factors. Furthermore, MARCO expression is significantly altered over the course of treatment with PD1 checkpoint inhibitors. These findings illustrate a novel myeloid subpopulation that drives tumor progression in glioblastomas, and suggest potential therapeutic targets to prevent their recruitment glioblastoma.
2020-12-23 | GSE141383 | GEO
Project description:BackgroundMacrophages are the most common infiltrating immune cells in gliomas and play a wide variety of pro-tumor and anti-tumor roles. However, the different subpopulations of macrophages and their effects on the tumor microenvironment remain poorly understood.MethodsWe combined new and previously published single-cell RNA-seq data from 98,015 single cells from a total of 66 gliomas to profile 19,331 individual macrophages.ResultsUnsupervised clustering revealed a pro-tumor subpopulation of bone marrow-derived macrophages characterized by the scavenger receptor MARCO, which is almost exclusively found in IDH1-wild-type glioblastomas. Previous studies have implicated MARCO as an unfavorable marker in melanoma and non-small cell lung cancer; here, we find that bulk MARCO expression is associated with worse prognosis and mesenchymal subtype. Furthermore, MARCO expression is significantly altered over the course of treatment with anti-PD1 checkpoint inhibitors in a response-dependent manner, which we validate with immunofluorescence imaging.ConclusionsThese findings illustrate a novel macrophage subpopulation that drives tumor progression in glioblastomas and suggest potential therapeutic targets to prevent their recruitment.
| S-EPMC8136167 | biostudies-literature
Project description:Scavenger receptors on the cell surface of macrophages play an important role in host defence through their ability to bind microbial ligands and induce phagocytosis. Concurrently, signal transduction pathways are initiated that aid in defence mechanisms against the invading microbe. Here we report on the function of scavenger receptor Marco (macrophage receptor with collagenous structure) during infection of zebrafish embryos with Mycobacterium marinum, a close relative of Mycobacterium tuberculosis. Morpholino knockdown demonstrates that Marco is required for the rapid phagocytosis of M. marinum following intravenous infection. Furthermore, gene expression analysis shows that Marco controls the initial transient pro-inflammatory response to M. marinum and remains a determining factor for the immune response signature at later stages of infection. Increased bacterial burden following marco knockdown indicates that this scavenger receptor is important for control of M. marinum growth, likely due to delayed phagocytosis and reduced pro-inflammatory signalling observed under conditions of Marco deficiency
2014-08-06 | GSE58230 | GEO
Project description:Eighteen independent neurospheres derived from patients affected by primary glioblastoma were grouped into “classical”, “mesenchymal” or “proneural” subtypes according to analysis of genetic lesions and gene expression profiling. Here we show that expression of the MET oncogene, encoding the tyrosine kinase receptor for HGF, associates with mesenchymal and proneural neurospheres (Met-pos-NS). Met expression is almost absent from classical neurospheres (Met-neg-NS), and mutually exclusive with amplification and expression of the EGF receptor gene. Met-pos-NS and Met-neg-NS display distinct growth factor requirements, differentiate along divergent pathways, and generate tumors with distinctive histological features. Met-pos-NS contain a variable percentage of Met positive (Methigh) and Met negative (Metneg) cells. After purification, only Methigh cells display clonogenic ability in vitro, and regenerate neurospheres containing both Methigh and Metneg cells. After in vivo transplantation, Methigh cells display highly enriched tumorigenic potential as compared with Metneg cells. At functional level, in Methigh cells, HGF concomitantly sustains proliferation, clonogenicity, expression of self-renewal markers, migration and invasion. These data show that Met is a functional marker of glioblastoma stem cells, and a candidate target for molecular diagnosis and therapy of a glioblastoma subset. 37 samples (17 replicate samples and 1 triplicate sample)
2012-10-05 | E-GEOD-36426 | biostudies-arrayexpress
Project description:Glycoproteomic screening indicates that core fucosylation activation is more highly enhancedin mesenchymal (MES) than in proneural (PN) glioblastoma cancer stem cells (GSCs) and this pattern is retained in subgroup-specific xenograftsand human patients’ samples. Most MES-restricted core fucosylated proteins are involved in therapeutically relevant pathological processes, such as extracellular matrix interaction and tumor invasion.
2022-11-09 | PXD033408 | Pride
Project description:To gain additional insight into the role of MARCO in dendritic cell activation and function, we profiled transcriptomes of mouse splenic dendritic cells obtained from MARCO deficient mice and their wild type counterparts under resting and activating conditions. Pure dendritic cells from the spleens of WT and MARCO KO mice were cultured overnight in PBS or Lipopolysaccharide (LPS). Gene expression profiling was performed using Affymetrix platform.
2014-02-18 | E-GEOD-55068 | biostudies-arrayexpress
Project description:In glioblastoma, a mesenchymal phenotype is associated with especially poor patient outcomes. Various glioblastoma microenvironmental factors and therapeutic interventions are purported drivers of the mesenchymal transition, but the degree to which these cues promote the same mesenchymal transitions and the uniformity of those transitions, as defined by molecular subtyping systems, is unknown. Here, we investigate this question by analyzing publicly available patient data, surveying commonly measured transcripts for mesenchymal transitions in glioma-initiating cells (GIC), and performing next-generation RNA sequencing of GICs. Analysis of patient tumor data reveals that TGFβ, TNFα, and hypoxia signaling correlate with the mesenchymal subtype more than the proneural subtype. In cultured GICs, the microenvironment-relevant growth factors TGFβ and TNFα and the chemotherapeutic temozolomide promote expression of commonly measured mesenchymal transcripts. However, next-generation RNA sequencing reveals that growth factors and temozolomide broadly promote expression of both mesenchymal and proneural transcripts, in some cases with equal frequency. These results suggest that glioblastoma mesenchymal transitions do not occur as distinctly as in epithelial-derived cancers, at least as determined using common subtyping ontologies and measuring response to growth factors or chemotherapeutics. Further understanding of these issues may identify improved methods for pharmacologically targeting the mesenchymal phenotype in glioblastoma.
2024-01-10 | GSE229136 | GEO
Project description:A mesenchymal transition occurs both during natural evolution of glioblastoma (GBM) and in response to therapy. However, the molecular mechanisms underlying mesenchymal differentiation are not well understood. We have found that the adhesion G protein-coupled receptor GPR56/ADGRG1 inhibits mesenchymal differentiation and radioresistance in glioblastoma stem-like initiating cells (GICs). Here, we have performed microarray analysis of parental- versus GPR56 knockout-GICs to identify gene expression changes upon GPR56 knockout
2017-10-31 | GSE104653 | GEO
Project description:A mesenchymal transition occurs both during natural evolution of glioblastoma (GBM) and in response to therapy. However, the molecular mechanisms underlying mesenchymal differentiation are not well understood. We have found that the adhesion G protein-coupled receptor, GPR56/ADGRG1, inhibits mesenchymal differentiation and radioresistance in glioblastoma stem-like initiating cells (GICs). Here, we have performed microarray analysis of control- versus GPR56 knockdown-GICs to characterize gene expression changes upon GPR56 knockdown and identify a gene expression signature associated to GPR56.
2017-10-01 | GSE94765 | GEO
Project description:<p>Glioblastoma (GBM) is a common and deadly form of brain tumor in adults. Dysregulated metabolism in GBM offers an opportunity to deploy metabolic interventions as precise therapeutic strategies. To identify the molecular drivers and the modalities by which different molecular subgroups of GBM exploit metabolic rewiring to sustain tumor progression, we interrogated the transcriptome, the metabolome, and the glycoproteome of human subgroup-specific GBM sphere-forming cells (GSC). L-fucose abundance and core fucosylation activation were elevated in mesenchymal (MES) compared with proneural GSCs; this pattern was retained in subgroup-specific xenografts and in subgroup-affiliated human patient samples. Genetic and pharmacological inhibition of core fucosylation significantly reduced tumor growth in MES GBM preclinical models. Liquid chromatography-mass spectrometry (LC-MS)-based glycoproteomic screening indicated that most MES-restricted core-fucosylated proteins are involved in therapeutically relevant GBM pathological processes, such as extracellular matrix interaction, cell adhesion, and integrin-mediated signaling. Selective L-fucose accumulation in MES GBMs was observed using preclinical minimally invasive PET, implicating this metabolite as a potential subgroup-restricted biomarker.Overall, these findings indicate that L-fucose pathway activation in MES GBM is a subgroup-specific dependency that could provide diagnostic markers and actionable therapeutic targets.</p><h4><strong>SIGNIFICANCE: </strong>Metabolic characterization of subgroup-specific glioblastoma (GBM) sphere-forming cells identifies the L-fucose pathway as a vulnerability restricted to mesenchymal GBM, disclosing a potential precision medicine strategy for targeting cancer metabolism.</h4><p><br></p><p><strong>Xenograft assays</strong> are reported in the current study <strong>MTBLS730</strong>.</p><p><strong>Stem cell and cell line assays</strong> are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS4708' rel='noopener noreferrer' target='_blank'><strong>MTBLS4708</strong></a>.</p>
2022-11-08 | MTBLS730 | MetaboLights