Glioma epileptiform activity and progression are driven by IGSF3 mediated potassium dysregulation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA914744 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22853104_1.fastq.gz | Fastqsanger.gz | |||
| SRR22853104_2.fastq.gz | Fastqsanger.gz | |||
| SRR22853105_1.fastq.gz | Fastqsanger.gz | |||
| SRR22853105_2.fastq.gz | Fastqsanger.gz | |||
| SRR22853106_1.fastq.gz | Fastqsanger.gz |
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Project description:Glioma epileptiform activity and progression are driven by IGSF3 mediated potassium dysregulation [mouse]
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Project description:Glioma epileptiform activity and progression are driven by IGSF3 mediated potassium dysregulation [human]
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Project description:Seizures are a pathophysiological feature of malignant glioma. Recent studies implicate peritumoral synaptic dysregulation as a driver of neuronal hyperactivity and tumor progression, however, the molecular mechanisms that govern these phenomena remain elusive. Using scRNA-seq and intraoperative patient ECoG recordings, we show that tumors from seizure patients are enriched for gene signatures regulating synapse formation. Employing a human-to-mouse in vivo functionalization pipeline to screen these gene sets, we identified IGSF3 as a mediator of glioma progression and dysregulated neural circuitry in the form of spreading depolarization (SD). Mechanistically, we discovered that IGSF3 interacts with Kir4.1 to suppress potassium buffering and found that seizure patients exhibit reduced expression of potassium handlers in proliferating tumor cells. In vivo imaging revealed dysregulated synaptic activity emanates from the tumor-neuron interface, which we confirmed in patients. Our studies reveal that tumor progression and seizures are enabled by ion dyshomeostasis and identify SD as a driver of disease.
2023-01-01 | GSE221534 | GEO
Project description:Seizures are a pathophysiological feature of malignant glioma. Recent studies implicate peritumoral synaptic dysregulation as a driver of neuronal hyperactivity and tumor progression, however, the molecular mechanisms that govern these phenomena remain elusive. Using scRNA-seq and intraoperative patient ECoG recordings, we show that tumors from seizure patients are enriched for gene signatures regulating synapse formation. Employing a human-to-mouse in vivo functionalization pipeline to screen these gene sets, we identified IGSF3 as a mediator of glioma progression and dysregulated neural circuitry in the form of spreading depolarization (SD). Mechanistically, we discovered that IGSF3 interacts with Kir4.1 to suppress potassium buffering and found that seizure patients exhibit reduced expression of potassium handlers in proliferating tumor cells. In vivo imaging revealed dysregulated synaptic activity emanates from the tumor-neuron interface, which we confirmed in patients. Our studies reveal that tumor progression and seizures are enabled by ion dyshomeostasis and identify SD as a driver of disease.
2023-01-01 | GSE221533 | GEO
Project description:Seizures are a frequent pathophysiological feature of malignant glioma. Recent studies implicate peritumoral synaptic dysregulation as a driver of brain hyperactivity and tumor progression; however, the molecular mechanisms that govern these phenomena remain elusive. Using scRNA-seq and intraoperative patient ECoG recordings, we show that tumors from seizure patients are enriched for gene signatures regulating synapse formation. Employing a human-to-mouse in vivo functionalization pipeline to screen these genes, we identify IGSF3 as a mediator of glioma progression and dysregulated neural circuitry that manifests as spreading depolarization (SD). Mechanistically, we discover that IGSF3 interacts with Kir4.1 to suppress potassium buffering and found that seizure patients exhibit reduced expression of potassium handlers in proliferating tumor cells. In vivo imaging reveals that dysregulated synaptic activity emanates from the tumor-neuron interface, which we confirm in patients. Our studies reveal that tumor progression and seizures are enabled by ion dyshomeostasis and identify SD as a driver of disease.
| S-EPMC9991983 | biostudies-literature
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Project description:Akt is a robust oncogene that plays key roles in the development and progression of many cancers, including glioma. We evaluated the differential propensities of the Akt isoforms toward progression in the well-characterized RCAs/Ntv-a mouse model of PDGFB-driven low grade glioma. A constitutively active myristoylated form of Akt1 did not induce high-grade glioma (HGG). In stark contrast, Akt2 and Akt3 showed strong progression potential with 78% and 97% of tumors diagnosed as HGG, respectively. We further revealed that significant variations in polarity and hydropathy values among the Akt isoforms in both the pleckstrin homology domain (P domain) and regulatory domain (R domain) were critical in mediating glioma progression. Gene expression profiles from representative Akt-derived tumors indicated dominant and distinct roles for Akt3, consisting primarily of DNA repair pathways. TCGA data from human GBM closely reflected the DNA repair function, as Akt3 was significantly correlated with a 76 gene signature DNA repair panel. Consistently, compared to Akt1 and Akt2 overexpression models, Akt3-expressing human GBM cells had enhanced activation of DNA repair proteins, leading to increased DNA repair and subsequent resistance to radiation and temozolomide. Given the wide range of Akt3-amplified cancers, Akt3 may represent a key resistance factor. 5 different experimental conditions were compared (including GFP, PDGFB, PDGFB in conjunciton with Akt1, Akt2, or Akt3) with 3 mice per treatment
2015-02-24 | E-GEOD-66177 | biostudies-arrayexpress
Project description:Insulin-like growth factor-binding protein 2 (IGFBP2) is increasingly recognized as a glioma oncogene, emerging as a target for therapeutic intervention. In this study, we used an integrative approach to characterizing the IGFBP2 network, combining transcriptional profiling of human glioma with validation in glial cells and the replication competent ASLV long terminal repeat with a splice acceptor/tv-a glioma mouse system. We demonstrated that IGFBP2 expression is closely linked to genes in the integrin and integrin-linked kinase (ILK) pathways and that these genes are associated with prognosis. We further showed that IGFBP2 activates integrin ?1 and down- stream invasion pathways, requires ILK to induce cell motility, and activates NF-?B. Most significantly, the IGFBP2/integrin/ILK/NF-?B network functions as a physiologically active signaling pathway in vivo by driving glioma progression; interfering with any point in the pathway markedly inhibits progression. The results of this study reveal a signaling pathway that is both targetable and highly relevant to improving the survival of glioma patients. We performed cDNA microarray analysis to compare two stably expressing cell lines originating from SNB19; two clones expressing a mutant form of IGFBP2 that cannot bind integrin (RGD ? RGE point mutation; referred to as RGE mutant); and two clones expressing wild-type IGFBP2. SNB19 clones transfected with empty vector were placed in the reference channel in each hybridization.
2012-02-02 | E-GEOD-35467 | biostudies-arrayexpress
Project description:In the present study, we applied a quantitative MS-based strategy to characterize the proteome and phosphoproteome in HRAS- or IDH1-driven glioma cells. We describe the driving roles of the MEK and PI3K signaling pathways in RAS-NHA cells, and uncover oncogenic signaling in other pathways. We highlight the interplay between the signaling cascades and show that inhibition of MEK and PI3K reverses phosphorylation signaling patterns driven by oncogenic RAS overexpression. Applying a histone hybrid chemical labeling method and high-resolution MS, we identified significant histone methylation, acetylation, and butyrylation changes in IDH1mut-NHA cells. Our results suggest a global transcriptional repressive state, consistent with the down-regulation of the proteome, transcriptome, and the DNA hyper-methylated state in IDH1mut-NHA cells. We provide a unique resource of altered proteins, phosphosites, and histone PTMs in RAS and IDH1 mutant astrocytoma cell lines, providing insight into oncogenesis in glioma beyond the transcriptomic level.
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