ZBTB18 hinders cytokine expression to impair microglia and macrophage recruitment and the establishment of a tumor-supportive microenvironment in glioblastoma
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ABSTRACT:
PROVIDER: PRJNA1036195 | ENA |
REPOSITORIES: ENA
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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 known to play an important role in glioblastoma progression, due to their massive recruitment in the tumor microenvironment and polarization to a tumor promoting phenotype. GAMs secrete a variety of cytokines, which promotes tumor cell growth and invasion while inhibiting an immune tumor response by other immune cells. Here, we demonstrate that ZBTB18, a transcriptional repressor with tumor suppressive function in glioblastoma, impairs the production of key cytokines, which functions as chemoattractant for GAMs. Consequently, we observe a reduced migration of GAMs when ZBTB18 is expressed by GBM cells, both in cell culture and in vivo experiments. Moreover, the presence of ZBTB18 halts GBMs cells-mediated GAMs polarization to a tumor suppressive phenotype characterized by a reduced engage in the oxidative phosphorylation pathway for energy supply. Thus, our findings suggest that therapeutic approaches to increase ZBTB18 expression in GBM cells could have a broad impact on both tumor cells and the surrounding immune microenvironment.
2024-10-08 | GSE227722 | GEO
Project description:ZBTB18 is a transcriptional repressor and tumor suppressor in glioblastoma (GBM). Specifically, it acts as a repressor of mesenchymal genes. ZBTB18 interacts with C-terminal binding proteins 1 and 2 through a VLDL motif. In GBM, ZBTB18 is cleaved the the calpain 2 intracellular proteases which generates truncated Nte and Cte short forms. Here we have investigated gene expression changes which occur upon the expression of ZBTB18 full lenght or ZBTB18 short form Nte (SF-Nte), as well as upon expression of the mutated counterparts which no longer interacts with CTBP1/2.
2022-06-20 | GSE184890 | GEO
Project description:This study set out to delineate gene expression programs that are differentially modulated in metastatic breast cancer cells with high versus low ability to further metastasize. To this end, the gene expression profiles of E0771GFP cells, M11GFP and M12GFP cells were determined. Analysis of these data sets identified ZBTB18 as a transcriptional repressor with lower activity in tumor cells that retain a high metastatic potential. To determine how ZBTB18 affects gene expression and chromatin organization, ZBTB18 was overexpressed in E0771GFP breast cancer cells. Gene expression profiles and differentially accessible DNA regions analyses were performed and identified Tgfbr2 as one of the genes most significantly repressed by ZBTB18. To determine the contribution of the TGFb1 -TGFBR2 signaling axis towards ZBTB18-mediated effects, E0771GFP cells overexpressing ZBTB18 were transduced with a doxycycline-inducible Tgfbr2 construct. These cells were then treated with doxycycline and recombinant TGFb1 or vehicle control and gene expression profiles were determined. These studies revealed that inhibition of ZBTB18 activity in tumor cells promotes metastasis by increasing chromatin accessibility and by enabling pro-metastatic TGFb1-TGFBR2-driven changes.
2022-12-22 | GSE195942 | GEO
Project description:This study set out to delineate gene expression programs that are differentially modulated in metastatic breast cancer cells with high versus low ability to further metastasize. To this end, the gene expression profiles of E0771GFP cells, M11GFP and M12GFP cells were determined. Analysis of these data sets identified ZBTB18 as a transcriptional repressor with lower activity in tumor cells that retain a high metastatic potential. To determine how ZBTB18 affects gene expression and chromatin organization, ZBTB18 was overexpressed in E0771GFP breast cancer cells. Gene expression profiles and differentially accessible DNA regions analyses were performed and identified Tgfbr2 as one of the genes most significantly repressed by ZBTB18. To determine the contribution of the TGFb1 -TGFBR2 signaling axis towards ZBTB18-mediated effects, E0771GFP cells overexpressing ZBTB18 were transduced with a doxycycline-inducible Tgfbr2 construct. These cells were then treated with doxycycline and recombinant TGFb1 or vehicle control and gene expression profiles were determined. These studies revealed that inhibition of ZBTB18 activity in tumor cells promotes metastasis by increasing chromatin accessibility and by enabling pro-metastatic TGFb1-TGFBR2-driven changes.
2022-12-22 | GSE195941 | GEO
Project description:We have identified the CTBP2 protein as a new ZBTB18 interactor. Here we have evaluated transcriptomic changes upon CTBP2 knockdown in the GBM cell line SNB19. Moreover, we have analyzed whether CTBP2 is required for ZBTB18-mediated gene repression.
2019-12-01 | GSE138890 | GEO
Project description:The differentiation of plasma cell is prescisely controlled by the key transcriptional program as well as epigenetic changes. Recently, we have identified, one zinc finger protein, Zbtb18, as a new regulator for B cell differentiation process. To investigate the molecular mechanisms of Zbtb18 during B cell differentiation program we employed the assay for transposase (Tn5) -accessible chromatin followed by deep sequencing (ATAC-Seq) in the sorted Control and Zbtb18 over-expressing B cells (B220+ CD138-) before and after anti-CD40 and IL-4 stimulation. Mice primary B cells were retrovially transduced with either control vector with RFP repoter or Zbtb18 with GFP repoter, and both were primed 2 days on the 40LB stroma cells before mixed 1:1 and then stimulated with anti-CD40 (10ug/ml) and IL-4 (10ng/ml) for 2 days. Activated B cells, B220+ CD138-, were sorted by BD AriaIII and followed by ATAC-seq protocol (Nat Methods. 2017 Oct;14(10):959-962).
2020-09-01 | GSE129657 | GEO
Project description:The transcriptional repressor ZBTB18 was overexpressed in the brain tumor xenoline JX6 by lentiviral transduction. Three independent transduction were performed (biological replicates) and analyzed by gene expression aray. Gene set enrichemnt analysis (GSEA) showed changes in the expression of mesenchymal signature. A subset of genes was further valiadted by qPCR. These results indicate a role of ZBTB18 as repressor of mesenchymal genes in Glioblastoma.
2017-04-04 | GSE97349 | GEO
Project description:The transcriptional repressor ZBTB18 was overexpressed in the brain tumor stem cell-like BTSC233 by lentiviral transduction. Three independent transduction were performed (biological replicates) and analyzed by gene expression aray. Gene set enrichemnt analysis (GSEA) showed changes in the expression of mesenchymal signature. A subset of genes was further valiadted by qPCR. These results indicate a role of ZBTB18 as repressor of mesenchymal genes in Glioblastoma.
2017-04-04 | GSE97347 | GEO
Project description:To understand the specific mechanism by which Foxj3 and Zbtb18 control RA-induced neural directional differentiation of ESCs, total mRNAs of Foxj3-ES and Zbtb18-ES were extracted and used for RNA seq and transcriptome analyses. Compared with the control, 1331 genes were differentially expressed (P < 0.05) by twofold in Foxj3-ES (557 were underexpressed and 774 were overexpressed), and 1175 genes were differentially expressed (P < 0.05) by twofold in Zbtb18-ESCs (548 were underexpressed and 627 were overexpressed). Through Gene ontology and gene co-expression network analysis, we identified four critical genes in the neural regulatory networks: Olig1, Zic5, Erbb2, and Olig2. Our study shows that Foxj3 and Zbtb18 could trigger the gene regulatory networks of neurodevelopment by mediating the expression of Olig1, Zic5, Erbb2, and Olig2.
2017-08-21 | GSE61748 | GEO