Single-nucleus and spatial landscape of the sub-ventricular zone in human glioblastoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE259378 | GEO | 2024/11/20
REPOSITORIES: GEO
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Project description:Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumor. GBM proximal to the lateral ventricles (LVs) is more aggressive, potentially due to subventricular zone (SVZ) contact. Despite this, crosstalk between GBM and neural stem/progenitor cells (NSC/NPCs) is not well understood. Using cell-specific proteomics, we show that LV-proximal GBM prevents neuronal maturation of NSCs through induction of senescence. Additionally, interaction with NPCs increases cathepsin B (CTSB) expression in GBM brain tumor initiating cells (BTICs). Lentiviral knockdown and recombinant protein experiments reveal both cell-intrinsic and soluble CTSB promote malignancy-associated BTIC phenotypes. Soluble CTSB stalls neuronal maturation in NPCs while promoting senescence, providing a link between LV-tumor proximity and neurogenesis disruption. Finally, we show LV-proximal CTSB upregulation in patients, showing the relevance of this crosstalk in human GBM biology. These results demonstrate the value of proteomic analysis in tumor microenvironment research and provide direction for new therapeutic strategies in GBM.
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Project description:A substantial body of evidence suggests that the initiation, progression, and recurrence of glioblastomas (GBM) are driven by a small subpopulation (1-5%) of cells within the tumor known as tumor-initiating cells or cancer stem cells (CSCs). GBM CSCs play a pivotal role in orchestrating drug resistance mechanisms and tumor relapse. As a prospective avenue for GBM intervention, targeted suppression of GBM CSCs holds promise. In this study, we identified novel rocaglate derivatives (rocaglate acyl sulfamides (Roc ASFs)) that can inhibit GBM CSCs with nanomolar (nM) EC50s. Our findings, supported by comparative dose-response assays and functional characterizations, demonstrate that these derivatives exert a robust, dose-dependent cytotoxic impact on GBM CSCs. Furthermore, our investigations into target identification have unveiled the DEAD box helicase DDX3X as a specific target of Roc ASFs. Inhibiting DDX3X using Roc ASF derivatives confers selective cytotoxicity to GBM CSCs. These findings suggest a promising therapeutic strategy for targeting GBM CSCs.
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Project description:Glioblastoma (GBM) is thought to be driven by a sub-population of cancer stem cells (CSCs) that self-renew and recapitulate tumor heterogeneity, yet remain poorly understood. Here we present a comparative epigenomic analysis of GBM CSCs that reveals widespread activation of genes normally held in check by Polycomb repressors. These activated targets include a large set of developmental transcription factors (TFs) whose coordinated activation is unique to the CSCs. We demonstrate that a critical factor in the set, ASCL1, activates Wnt signaling by repressing the negative regulator DKK1. We show that ASCL1 is essential for maintenance and in vivo tumorigenicity of GBM CSCs. Genomewide binding profiles for ASCL1 and the Wnt effector LEF1 provide mechanistic insight and suggest widespread interactions between the TF module and the signaling pathway. Our findings demonstrate regulatory connections between ASCL1, Wnt signaling and collaborating TFs that are essential for the maintenance and tumorigenicity of GBM CSCs. Two replicates for MGG4, MGG6, MGG23 and NS; four replicates for MGG8
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Project description:Glioblastoma (GBM) is thought to be driven by a sub-population of cancer stem cells (CSCs) that self-renew and recapitulate tumor heterogeneity, yet remain poorly understood. Here we present a comparative epigenomic analysis of GBM CSCs that reveals widespread activation of genes normally held in check by Polycomb repressors. These activated targets include a large set of developmental transcription factors (TFs) whose coordinated activation is unique to the CSCs. We demonstrate that a critical factor in the set, ASCL1, activates Wnt signaling by repressing the negative regulator DKK1. We show that ASCL1 is essential for maintenance and in vivo tumorigenicity of GBM CSCs. Genomewide binding profiles for ASCL1 and the Wnt effector LEF1 provide mechanistic insight and suggest widespread interactions between the TF module and the signaling pathway. Our findings demonstrate regulatory connections between ASCL1, Wnt signaling and collaborating TFs that are essential for the maintenance and tumorigenicity of GBM CSCs. Epigenomic profiling of glioblastoma stem cells
2013-05-28 | E-GEOD-46015 | biostudies-arrayexpress
Project description:PD-L1 Inhibitor Regulates the miR-33a-5p/PTEN Signaling Pathway and Can Be Targeted to Sensitize Glioblastomas to Radiation. Glioblastoma (GBM) is the most common and lethal brain tumor in adults. Ionizing radiation (IR) is a standard treatment for GBM patients and results in DNA damage. However, the clinical efficacy of IR is limited due to therapeutic resistance. The programmed death ligand 1 (PD-L1) blockade has a shown the potential to increase the efficacy of radiotherapy by inhibiting DNA damage and repair responses. The miR-33a-5p is an essential microRNA that promotes GBM growth and self-renewal. In this study, we investigated whether a PD-L1 inhibitor (a small molecule inhibitor) exerted radio-sensitive effects to impart an anti-tumor function in GBM cells by modulating miR-33a-5p. U87 MG cells and U251 cells were pretreated with PD-L1 inhibitor. The PD-L1 inhibitor-induced radio-sensitivity in these cells was assessed by assaying cellular apoptosis, clonogenic survival assays, and migration. TargetScan and luciferase assay showed that miR-33a-5p targeted the phosphatase and tensin homolog (PTEN) 3' untranslated region. The expression level of PTEN was measured by western blotting, and was also silenced using small interfering RNAs. The levels of DNA damage following radiation was measured by the presence of γ-H2AX foci, cell cycle, and the mRNA of the DNA damage-related genes, BRCA1, NBS1, RAD50, and MRE11. Our results demonstrated that the PD-L1 inhibitor significantly decreased the expression of the target gene, miR-33a-5p. In addition, pretreatment of U87 MG and U251 cells with the PD-L1 inhibitor increased radio-sensitivity, as indicated by increased apoptosis, while decreased survival and migration of GBM cells. Mir-33a-5p overexpression or silencing PTEN in U87 MG and U251 cells significantly attenuated PD-L1 radiosensitive effect. Additionally, PD-L1 inhibitor treatment suppressed the expression of the DNA damage response-related genes, BRCA1, NBS1, RAD50, and MRE11. Our results demonstrated a novel role for the PD-L1 inhibitor in inducing radio- sensitivity in GBM cells, where inhibiting miR-33a-5p, leading to PTEN activated, and inducing DNA damage was crucial for antitumor immunotherapies to treat GBM.
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Project description:Glioblastoma (GBM, WHO grade IV) is an aggressive, primary brain tumor. Despite gross surgery and forceful radio- and chemotherapy, survival of GBM patients did not improve over decades. Several studies reported transcription deregulation in GBMs but regulatory mechanisms driving overexpression of GBM-specific genes remain largely unknown. Transcription in open chromatin regions is directed by transcription factors (TFs) that bind to specific motifs, recruit co-activators/repressors and a transcriptional machinery. Identification of GBM-related TFs-gene regulatory networks may reveal new, targetable mechanisms of gliomagenesis.
2023-03-01 | GSE206357 | GEO
Project description:Glioblastoma (GBM) is thought to be driven by a sub-population of cancer stem cells (CSCs) that self-renew and recapitulate tumor heterogeneity, yet remain poorly understood. Here we present a comparative epigenomic analysis of GBM CSCs that reveals widespread activation of genes normally held in check by Polycomb repressors. These activated targets include a large set of developmental transcription factors (TFs) whose coordinated activation is unique to the CSCs. We demonstrate that a critical factor in the set, ASCL1, activates Wnt signaling by repressing the negative regulator DKK1. We show that ASCL1 is essential for maintenance and in vivo tumorigenicity of GBM CSCs. Genomewide binding profiles for ASCL1 and the Wnt effector LEF1 provide mechanistic insight and suggest widespread interactions between the TF module and the signaling pathway. Our findings demonstrate regulatory connections between ASCL1, Wnt signaling and collaborating TFs that are essential for the maintenance and tumorigenicity of GBM CSCs. Histone modification profiling for multiple marks by ChIP-Seq in untreated glioblastoma cancer stem cells, glioblastoma non-stem cells and neural stem cells
2013-05-28 | E-GEOD-46014 | biostudies-arrayexpress
Project description:Background: Glioblastoma multiforme (GBM) is the most aggressive and most lethal primary malignant brain tumor, correlated with survival rates of less than one year from the time of diagnosis. Current surgical procedure attempts to remove the bulk of the tumor mass, whereas GBM frequently recurs within 1-3cm from the primary tumor resection site. Molecular mechanisms involved in the recurrence of the tumor are still poorly understood. The aim of the study was to define the molecular signature of GBM surrounding white matter (WM) in order to better understand the molecular mechanisms involved with tumor relapse. Material & Methods: Human GBM tumor bulk and surrounding tissue (1-3cm from the border of the tumor) were obtained from five patients who underwent total tumour resection, while normal white matter was harvested from patients who underwent surgical procedure for nonmalignant pathologies. Samples were processed for hybridization on the Affymetrix Human U133A arrays and data were examined with the GeneSpring analysis software. Results: Gene expression analysis of the samples was done in 2 independent steps. First, molecular profiling comparison of GBM surrounding WM and normal WM resulted in 59 genes differentially expressed between both tissues. Among these, numerous genes expressed by mature neural cells were down-regulated in GBM surrounding WM, while gene products supporting invasion were overexpressed. Moreover, KLRC1, a specific natural killer receptor naturally involved in the activation of antitumoral cells was drastically repressed in GBM surrounding WM, suggesting that the antitumoral immune surveillance is compromised in this tissue. Second, we focused our study on genes specifically regulated in GBM periphery respectively to GBM core. The highest up-regulated gene in GBM surrounding tissue encodes for DTX4, a regulator of NOTCH signalling pathway described for its key role in maintaining neural progenitors in an uncommitted state. Conclusion: This study revealed unique molecular characteristics of GBM surrounding tissue, showing the dysregulation of genes involved in immune surveillance along with genes associated to stemness maintenance. All together, these data may help to understand the molecular mechanisms associated with GBM recurrence This study attempted to define the molecular characteristics of the GBM surrounding tissue. To this end, GBM tumor samples were obtained from 5 patients who underwent total tumor resection. Surrounding tumor mass tissue was retrieved in all cases from not infiltrated white matter sited at 2 cm from the macroscopic tumor border. Furthermore, control white matter biopsies were harvested from patients operated on for deep intracerebral cavernomas. Each sample was hybridized onto Affymetrix human U133 arrays. For each patient, tumor core sample and surrounding tissue were harvested and are identified with the same suffix number. In 2 cases, (patients 3 and 4), two tumor peripheral tissue samples were harvested and are identified with the same number followed by "R" (replicate).
2009-06-15 | E-GEOD-13276 | biostudies-arrayexpress
Project description:Background Despite maximal therapy with surgery, chemotherapy and radiotherapy, glioblastoma multiforme (GBM) patients have a median survival of only 15 months. Almost all patients inevitably experience symptomatic tumor recurrence. A hallmark of this tumor type is the large heterogeneity between patients and within tumors itself which relate to failure of standardized tumor treatment. In this study, tissue samples of paired primary and recurrent GBM tumors were investigated to identify individual factors related to tumor progression. Methods Paired primary and recurrent GBM tumor tissues from 8 patients were investigated with a multi-omics approach using transcriptomics, proteomics and phosphoproteomics. Results In the studied patient cohort, large variations between and within patients are observed for all omics analyses. A few pathways affected at the different omics levels partly overlapped if patients are analyzed at the individual level, such as synaptogenesis (containing the SNARE complex) and cholesterol metabolism. Phosphoproteomics revealed increased STMN1(S38) phosphorylation that relates to ERBB4 signaling. A pathway tool has been developed to visualize and compare the different omics datasets per patient and showed potential therapeutic drugs, such as abobotulinumtoxina and afatinib, that target these affected pathways. Afatinib targeting ERBB4 signaling is currently in clinical trials for GBM. Conclusions Large variation on all omics levels exist between and within GBM patients. Therefore, it will be rather unlikely to find a drug treatment that would fit all patients. Instead a multi-omics approach can be used to identify affected pathways on the individual patient level and select potential treatment options.
2020-11-17 | PXD017952 | Pride