Tumor-Associated Microglia Secrete Extracellular ATP to Support Glioblastoma Progression
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PROVIDER: PRJNA1150205 | ENA |
REPOSITORIES: ENA
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Project description:Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis and high recurrence rates. The complex immune microenvironment of GBM is highly infiltrated by tumor-associated microglia and macrophages (TAMs). TAMs are known to be heterogeneous in their functional and metabolic states and can transmit either pro-tumoral or anti-tumoral signals to glioma cells. Here, we performed bulk RNA-seq and single-cell RNA-seq on GBM patient samples, which revealed increased ATP synthase expression and oxidative phosphorylation (OXPHOS) activity in TAMs located in the tumor core relative to the tumor periphery. Both in vitro and in vivo models displayed similar trends of augmented TAM mitochondrial activity, along with elevated mitochondrial fission, glucose uptake, mitochondrial membrane potential, and extracellular ATP (eATP) production by TAMs in the presence of GBM cells. Tumor-secreted factors, including GM-CSF, induced the increase in TAM eATP production. Elevated eATP in the GBM microenvironment promoted glioma growth and invasion by activating the P2X purinoceptor 7 (P2X7R) on glioma cells. Inhibition of the eATP-P2X7R axis attenuated tumor cell viability in vitro and reduced tumor size and prolonged survival in glioma-bearing mouse models. Overall, this study revealed elevated TAM-derived eATP in GBM and provided the basis for targeting the eATP-P2X7R signaling axis as a therapeutic strategy in GBM.
2024-08-30 | GSE275293 | GEO
Project description:The 18 kDa translocator protein (TSPO) emerges as an important PET biomarker to assess the tumor microenvironment (TME) in glioblastoma. However, various cellular sources hamper interpretation and biological understanding of TSPO and other immune biomarkers in the TME. Thus, we established a novel method, combining immunomagnetic cell sorting after radiotracer injection (scRadiotracing) with 3D histology via light sheet microscopy and proteomics to dissect cellular allocation of TSPO enrichment in glioblastoma. Single tumor cells of implanted SB28 glioblastoma mice indicated 1.37-fold higher TSPO tracer uptake and 1.46-fold higher TSPO protein expression levels when compared to tumor associated microglia/macrophages (TAMs). Using proteomics, we compared the proteome of tumor associated microglia/macrophages (TAMs), Tumor tissue (TT) and control microglia from WT mice without glioblastoma. This analysis identified TAM specific targets for PET radioligand development with additional potential to monitor diverse TAM subpopulations in vivo. In summary, our data indicate that tumor cells need to be acknowledged as the main contributor to TSPO as a biomarker in glioblastoma. Combining cellular tracer uptake measures with 3D histology facilitates precise allocation of complex PET signal sources and will serve to validate novel TAM specific radioligands.
2023-10-30 | PXD044033 | Pride
Project description:Background Glioblastomas are the most common and lethal primary brain tumors. Microglia, the resident immune cells of the brain survey their environment and respond to pathogens, toxins, and tumors. Glioblastoma cells communicate with microglia, in part by releasing extracellular vesicles (EVs). Despite the presence of large numbers of microglia in glioblastoma, the tumors continue to grow, and these neuroimmune cells appear incapable of keeping the tumor in check. To understand this process, we analyzed gene expression in microglia interacting with glioblastoma cells. Methods We used RNASeq to analyze the expression patterns of genes involved in key microglial function of microglia in mice with glioblastoma. We focused on microglia that had taken up tumor-derived EVs and therefore were within and immediately adjacent to the tumor. Results We show that these microglia have downregulated expression of genes involved in sensing tumor cells and tumor-derived danger signals, as well as genes used for tumor killing. In contrast, expression of genes involved in facilitating tumor spread was upregulated. These changes appear to be in part EV-mediated, since intracranial injection of EVs in normal mice led to similar transcriptional changes in microglia. We observed a similar microglial transcriptomic signature when we analyzed datasets from human patients with glioblastoma. Conclusion Our data define a MicrogliaGlioblastoma specific phenotype, whereby glioblastomas have hijacked gene expression in the neuroimmune system to favor avoiding tumor sensing, suppressing the immune response, clearing a path for invasion and enhancing tumor propagation. For further exploration we developed an interactive online tool at www.glioma-microglia.com with all expression data and additional functional and pathway information for each gene.
2020-04-22 | GSE106775 | GEO
Project description:Extracellular ATP is among molecules promoting microglia activation and inducing the release of extracellular vesicles (EVs), which are potent mediators of intercellular communication between microglia and the microenvironment. We previously showed that EVs produced under ATP stimulation (ATP-EVs) propagate a robust inflammatory reaction among astrocytes and microglia in vitro and in mice with subclinical neuroinflammation. However, the proteome of EVs released upon ATP stimulation has not yet been elucidated. In this study we applied a label free proteomic approach to characterize the proteome of EVs released constitutively and during microglia activation with ATP. We show that ATP drives sorting in EVs of a set of proteins implicated in cell adhesion/extracellular matrix organization, autophagy-lysosomal pathway and cellular metabolism, that may influence the response of recipient astrocytes to EVs. These data provide new clues to molecular mechanisms involved in microglia response to ATP and in microglia signalling to the environment via EVs.
2018-10-24 | PXD007650 | Pride
Project description:Background. Glioma associated macrophages/microglia (GAMs) are massively recruited to the tumor site where they commit to a tumor promoting phenotype, driving glioblastoma progression. GAMs secrete several factors that facilitate tumor proliferation and invasion, and prevent an effective immune response against glioblastoma. Here, we investigate how the tumor suppressor ZBTB18 affects GAMs and ultimately shapes the tumor microenvironment. Methods. The regulation of cytokine expression and secretion was assessed by gene expression and cytokine arrays. The effect of ZBTB18 expression on microglia properties was investigated in vivo in mouse xenografts and by RNAseq of microglia cells conditioned with the medium of ZBTB18-expressing patient-derived GBM cells. The analysis was further extended to TAM scRNAseq data (GBMap). Results. Here, we demonstrate that ZBTB18, a transcriptional repressor with tumor suppressive function in glioblastoma, impairs the production of key chemokines responsible for GAM recruitment. Consistently, we observe a reduced migration of GAMs towards ZBTB18-expressing glioblastoma cells, both in cell culture and in vivo experiments. Moreover, RNA sequencing analysis shows that the presence of ZBTB18 in glioblastoma cells alters the commitment of conditioned microglia, suggesting the loss of the immunosuppressive phenotype. Conclusions. Our data indicate that, by blocking the release of key cytokines, ZBTB18 modifies microglia behavior, counteracting their tumor-promoting function. Thus, therapeutic approaches to increase ZBTB18 expression in glioblastoma cells could represent an effective adjuvant to immunotherapy in the treatment of this kind of tumor.
2024-10-08 | GSE247079 | GEO
Project description:Three-dimensional regulatory hubs support oncogenic programs in glioblastoma
| PRJNA1081944 | ENA
Project description:Glioblastoma Hijacks Microglial Gene Expression to Support Tumor Growth
| PRJNA417971 | ENA
Project description:Three-dimensional regulatory hubs support oncogenic programs in glioblastoma
| PRJNA1090165 | ENA
Project description:Microglia, the brain resident macrophages, play a key role in the regulation of brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival. We have identified a new function of microglia as critical modulators of neuronal activity and associated behavioral responses in mice. We show that microglia respond to neuronal activation and that ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. The suppressive impact of microglia on neuronal activation occurs in a highly localized fashion and depends on the ability of microglia to sense and catabolize extracellular ATP. ATP, which can be released upon neuronal activation by neurons and astrocytes, triggers the recruitment of microglia protrusions and is converted by the microglial ATP-hydrolyzing enzyme CD39 and CD73 into AMP and adenosine, a potent suppressor of neuronal activity. We show that the microglial sensing of ATP, the ensuing production of adenosine, and the adenosine-mediated control of neuronal response via the A1R are essential for the microglia-mediated regulation of neuronal activity and animal behavior. Our findings suggest that this microglia-driven negative feedback mechanism operates in a fashion similar to inhibitory neurons and plays an essential role in protecting the brain from excessive activation in health and diseases.
2020-08-18 | GSE149897 | GEO