A functional subpopulation of human glioma associated macrophages linked to malignant glioma progression [mtscATAC-seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE276283 | GEO | 2025/08/01
REPOSITORIES: GEO
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Project description:Immune cells accumulating in the microenvironment of malignant tumors are tumor-educated, and contribute to its growth, progression and evasion of antitumor immune responses. Glioblastoma (GBM), the common and most malignant primary brain tumor in adults, shows considerable accumulation of resident microglia and peripheral macrophages, and their polarization into tumor-supporting cells. There are controversies regarding a functional phenotype of glioma-associated microglia/macrophages (GAMs) due to a lack of consistent markers. Previous categorization of GAM polarization towards the M2 phenotype has been found inaccurate because of oversimplification of highly complex and heterogeneous responses. In this study we characterized functional responses and gene expression in mouse and human microglial cultures exposed to fresh conditioned media (GCM) from human U87 and LN18 glioma cells. Functional analyses revealed mutual communication reflected by strong stimulation of glioma invasion by microglial cells and increased microglial phagocytosis after GCM treatment. To define transcriptomic markers of GCM-activated microglia, we performed selected and global gene expression analyses of stimulated microglial cells. We found activated pathways associated with immune-evasion and TGF signaling. We performed computational comparison of the expression patterns of GAMs from human GBMs and rodent experimental gliomas to select genes consistently changed in different datasets. The analyses of marker genes in GAMs from different experimental models and clinical samples revealed only a small set of common genes, which reflects variegated responses in clinical and experimental settings. We discuss potential sources of the observed differences and stress a great need for definitive elucidation of a functional state of GAMs.
2018-04-20 | GSE113370 | GEO
Project description:The tumor microenvironment of glioblastoma (GBM) is characterized by a high proportion of glioma-associated macrophages/microglia (GAMs). We performed spatial analysis (Visium) to profile GAMs in human GBM.
2025-04-11 | GSE273432 | GEO
Project description:Background: Glioma-associated macrophages (GAMs) are one of the most important cellular components in the tumor immune microenvironment (TIME). GAMs display a mostly M2-like phenotype with anti-inflammatory features, which is closely related to the malignancy and progression of cancers. Extracellular vesicles derived from GAMs (GAM-EVs), which are important components of the TIME, contain a variety of microRNAs (miRNAs). These miRNAs play a crucial role in communication between tumor cells and GAMs. In this study, we aimed to explore the effect of GAM-EVs on the malignancy and progression of glioblastoma multiforme (GBM) through miRNA-mediated communication and its possible signaling pathway. Methods: The GBM and LGG data from The Cancer Genome Atlas (TCGA) were analyzed, and the immunological features of 12 clinical glioma samples, including GBM and low-grade glioma (LGG) samples, were estimated by immunohistochemistry. To evaluate the changes induced by M2-EVs compared to M1-EVs, the human GBM cell lines U87MG and A172 were cocultured with M2-EVs and M1-EVs, and their epithelial-mesenchymal transition (EMT) behaviors were investigated. The contents of M2-EVs and M1-EVs were determined by miRNA sequencing, and the differences were analyzed. Then, the EMT signatures were evaluated after a miRNA mimic was transfected into GBM cells. Six databases were used to predict the targets of the miRNA. Human GBM cell lines with interference and overexpression of the most valuable candidate miRNA targets were established. The related signaling pathways were further explored. Finally, an orthotopic homograft mouse model was employed to verify the results of the in vitro experiments. Results: The immunosuppressive GAM genes were upregulated in GBM compared with LGG, showing that the TIME of GBM is more immunosuppressive. To explore the effect of the immunosuppressive GAMs and TIME on the progression of GBM, we established immunostimulatory (M1-like) and immunosuppressive (M2-like) GAMs and compared the differences in their EVs. The migration and invasion of U87MG and A172 cells were enhanced under coculture with M2-EVs. MiR-146a-5p was deficient in M2-EVs compared with M1-EVs. Upon treatment with the miR-146a-5p mimic, the migration and invasion abilities of GBM cells were weakened, and the EMT signature was correspondingly decreased. According to the database prediction, tumor necrosis factor receptor-associated factor 6 (TRAF6) and interleukin 1 receptor-associated kinase 1 (IRAK1) are the targets of miR-146a-5p. TRAF6 is an E3 ubiquitin ligase, and IRAK1 is the substrate. Bimolecular fluorescence complementation (BiFC) and coimmunoprecipitation assays confirmed interactions between TRAF6 and IRAK1. Interference with both TRAF6 and IRAK1 expression weakened but overexpression of both TRAF6 and IRAK1 promoted the EMT behaviors of GBM cells. The TRAF6-Glioma-associated macrophages (GAMs) are pivotal chains in the tumor immune microenvironment (TIME). GAMs mostly display M2-like phenotypes with anti-inflammatory features related to the malignancy and progression of cancers. Extracellular vesicles derived from immunosuppressive GAMs (M2-EVs), the essential components of the TIME, greatly impact the malignant behavior of GBM cells. M1- or M2-EVs were isolated in vitro, and human GBM cell invasion and migration were reinforced under M2-EV treatment. Signatures of the epithelial-mesenchymal transition (EMT) were also enhanced by M2-EVs. Compared with M1-EVs, miR-146a-5p, considered the key factor in TIME regulation, was deficient in M2-EVs according to miRNA-sequencing. When the miR-146a-5p mimic was added, EMT signatures and the invasive and migratory abilities of GBM cells were correspondingly weakened. Public databases predicted the miRNA binding targets and interleukin 1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6) were screened as miR-146a-5p binding genes. Bimolecular fluorescent complementation and coimmunoprecipitation confirmed interactions between TRAF6 and IRAK1. The correlation between TRAF6 and IRAK1 was evaluated with immunofluorescence (IF)-stained clinical glioma samples. The TRAF6-IRAK1 complex is the switch and the brake that modulates IKK complex phosphorylation and NF-κB pathway activation, as well as the EMT behaviors of GBM cells. Furthermore, a homograft nude mouse model was explored and mice transplanted with TRAF6/IRAK1-overexpressing glioma cells had shorter survival times while mice transplanted with glioma cells with miR-146a-5p overexpression or TRAF6/IRAK1 knockdown lived longer. This work indicated that in the TIME of GBM, the deficiency of miR-146a-5p in M2-EVs enhances tumor EMT through disinhibition of the TRAF6-IRAK1 complex and IKK-dependent NF-κB signaling pathway providing a novel therapeutic strategy targeting the TIME of GBM.
2023-06-28 | GSE212171 | GEO
Project description:Introduction: Glioma-associated microglia/macrophages (GAM) constitute the predominant immune cell population in glioblastoma (GB). Both GB cells and GAM exhibit upregulated mTOR signaling. This study aimed to investigate the effects of pharmacological mTOR inhibition (mTORi) specifically on GAM.Materials and Methods: We conducted a comprehensive analysis of the GAM phenotype, including whole transcriptome analyses and cytokine profiling. Effects were investigated in a tumor cell/GAM co-culture model under mTORi with rapamycin or torin2 or under treatment with temozolomide, the standard chemotherapy agent for GB patients.Results: In our in vitro model, mTORi had significant effects on central biological functions of GAM, resulting in reduced proliferation and oxygen consumption. Additionally, treatment with mTORi induced a pro-inflammatory phenotype in microglial cells.Conclusions: Our findings demonstrate the profound relevance of mTOR signaling on GAM biology. Moreover, they provide rationales for therapeutic interventions targeting mTOR signaling specifically in GAM as a potential novel treatment strategy.
2025-07-28 | GSE242829 | GEO
Project description:Glioma vascular cells (GVC) from high-grade IV gliomas (HG) are molecularly and functionally distinct from normal brain EC, and secrete higher levels of pro-tumorigenic factors that promote glioma growth and progression. However, it remains unclear whether GVC from Low- Grade II/II gliomas (LG) also express pro-tumorigenic factors, and to what extent they functionally contribute to glioma growth. Here, we profile the transcriptomes of GVC from IDH-mutant (mIDH) LG and IDH-wildtype (wIDH) HG and show that they exhibit significant molecular and functional heterogeneity. LG-GVC show enrichment of extracellular matrix and cell cycle-related gene sets and sensitivity to anti-angiogenic drugs, whereas HG-GVC display an increase in immune response-related gene sets and anti-angiogenic resistance. Strikingly, conditioned media from LG-GVC inhibits the growth of wIDH glioblastoma cells, whereas HG-GVC promotes growth. In vivo co-transplantation of LG-GVC with tumor cells reduces growth, whereas HG-GVC enhances tumor growth in orthotopic xenografts. We identify ASPORIN (ASPN), a small leucine-rich repeat proteoglycan, enriched in LG-GVC as a growth suppressor of wIDH glioblastoma cells in vitro and in vivo. Together, these findings indicate that GVC from LG and HG gliomas are heterogeneous and differentially regulate tumor growth.
2024-07-10 | GSE236570 | GEO
Project description:Glioma vascular cells (GVC) from high-grade IV gliomas (HG) are molecularly and functionally distinct from normal brain EC, and secrete higher levels of pro-tumorigenic factors that promote glioma growth and progression. However, it remains unclear whether GVC from Low- Grade II/II gliomas (LG) also express pro-tumorigenic factors, and to what extent they functionally contribute to glioma growth. Here, we profile the transcriptomes of GVC from IDH-mutant (mIDH) LG and IDH-wildtype (wIDH) HG and show that they exhibit significant molecular and functional heterogeneity. LG-GVC show enrichment of extracellular matrix and cell cycle-related gene sets and sensitivity to anti-angiogenic drugs, whereas HG-GVC display an increase in immune response-related gene sets and anti-angiogenic resistance. Strikingly, conditioned media from LG-GVC inhibits the growth of wIDH glioblastoma cells, whereas HG-GVC promotes growth. In vivo co-transplantation of LG-GVC with tumor cells reduces growth, whereas HG-GVC enhances tumor growth in orthotopic xenografts. We identify ASPORIN (ASPN), a small leucine-rich repeat proteoglycan, enriched in LG-GVC as a growth suppressor of wIDH glioblastoma cells in vitro and in vivo. Together, these findings indicate that GVC from LG and HG gliomas are heterogeneous and differentially regulate tumor growth.
2024-07-10 | GSE236569 | GEO
Project description:Glioma vascular cells (GVC) from high-grade IV gliomas (HG) are molecularly and functionally distinct from normal brain EC, and secrete higher levels of pro-tumorigenic factors that promote glioma growth and progression. However, it remains unclear whether GVC from Low- Grade II/II gliomas (LG) also express pro-tumorigenic factors, and to what extent they functionally contribute to glioma growth. Here, we profile the transcriptomes of GVC from IDH-mutant (mIDH) LG and IDH-wildtype (wIDH) HG and show that they exhibit significant molecular and functional heterogeneity. LG-GVC show enrichment of extracellular matrix and cell cycle-related gene sets and sensitivity to anti-angiogenic drugs, whereas HG-GVC display an increase in immune response-related gene sets and anti-angiogenic resistance. Strikingly, conditioned media from LG-GVC inhibits the growth of wIDH glioblastoma cells, whereas HG-GVC promotes growth. In vivo co-transplantation of LG-GVC with tumor cells reduces growth, whereas HG-GVC enhances tumor growth in orthotopic xenografts. We identify ASPORIN (ASPN), a small leucine-rich repeat proteoglycan, enriched in LG-GVC as a growth suppressor of wIDH glioblastoma cells in vitro and in vivo. Together, these findings indicate that GVC from LG and HG gliomas are heterogeneous and differentially regulate tumor growth.
2024-07-10 | GSE236568 | GEO
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:Glioma associated Macrophages (GAMs) are the most abundant immune cell type within diffuse gliomas and their density correlates with poorer prognosis. GAMs consist of resident microglia and bone marrow derived (BDM) cells and increased BDM infiltration is thought to be associated with disease progression however no definitive human marker of BDM exists. This is particularly true of LGGs, In this study we perform multicompartmental sampling and analyse GAMs from the perspective of gene regulatory networks. We show that GAMs and BDMs consist of distinct GRNs driven by the same master transcription factor SPI1, and that an increased activation of the blood derived SPI1 signature is associated with poorer prognosis in LGGs. Defining GAMs in terms of GRNs instead of marker genes alone permits a better understanding of the transcirptional programs that drive disease progression in diffuse gliomas.
2023-06-30 | E-MTAB-12528 | biostudies-arrayexpress
Project description:Purpose: Targeting immunosuppressive and pro-tumorigenic glioblastoma-associated macrophages and microglial cells (GAMs) has great potential to improve patient outcomes. Colony stimulating factor-1 receptor (CSF1R) has emerged as a promising target for reprogramming anti-inflammatory M2-like GAMs. However, treatment data on patient-derived, tumor-educated GAMs and their influence on the adaptive immunity are lacking.
Experimental Design: CD11b+-GAMs freshly isolated from patient tumors were treated with CSF1R-targeting drugs PLX3397, BLZ945, and GW2580. Phenotypical changes upon treatment were assessed using RNAseq. Changes in GAM activation were confirmed in a complex patient-derived 3D tumor organoid model serving as a tumor avatar.
Results: The most effective reprogramming of GAMs was observed upon GW2580 treatment, which led to the downregulation of M2-related markers, IL-6, and IL-10, ERK1/2 and MAPK signaling pathways, while M1-like markers and gene set enrichment indicating activated MHC-II presentation were substantially increased. Moreover, treatment of patient-derived glioblastoma organoids with GW2580 confirmed successful reprogramming.
| EGAS00001007466 | EGA