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Glioma epileptiform activity and progression are driven by IGSF3 mediated potassium dysregulation [human]

ABSTRACT: Glioma epileptiform activity and progression are driven by IGSF3 mediated potassium dysregulation [human]

PROVIDER: PRJNA914867 | ENA |

REPOSITORIES: ENA

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			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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Glioma epileptiform activity and progression are driven by IGSF3 mediated potassium dysregulation

Project description:Glioma epileptiform activity and progression are driven by IGSF3 mediated potassium dysregulation

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Project description:Glioma epileptiform activity and progression are driven by IGSF3 mediated potassium dysregulation [mouse]

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Glioma epileptiform activity and progression are driven by IGSF3 mediated potassium dysregulation [human]

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.

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Glioma epileptiform activity and progression are driven by IGSF3 mediated potassium dysregulation [mouse]

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Glioma epileptiform activity and progression are driven by IGSF3-mediated potassium dysregulation.

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.

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Glioma epileptiform activity and progression are driven by IGSF3 mediated potassium dysregulation

Project description:This SuperSeries is composed of the SubSeries listed below.

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PTBP1 Lactylation Promotes Glioma Stem Cell Maintenance through PFKFB4-Driven Glycolysis

Project description:Longstanding evidence implicates glioma stem cells (GSCs) as the major driver for glioma propagation and recurrence. GSCs have a distinctive metabolic landscape characterized by elevated glycolysis. Lactate accumulation resulting from enhanced glycolytic activity can drive lysine lactylation to regulate protein functions, suggesting that elucidating the lactylation landscape in GSCs could provide insights into glioma biology. Herein, we demonstrated that global lactylation was significantly elevated in GSCs compared to differentiated glioma cells (DGCs). PTBP1, a central regulator of RNA processing, was hyperlactylated in GSCs, and SIRT1 induced PTBP1 delactylation. PTBP1-K436 lactylation supported glioma progression and GSC maintenance. Mechanistically, K436 lactylation inhibited PTBP1 proteasomal degradation by attenuating the interaction with TRIM21. Moreover, PTBP1 lactylation enhanced its RNA-binding capacity and facilitated PFKFB4 mRNA stabilization, which further increased glycolysis. Together, these findings uncovered a lactylation-mediated mechanism in GSCs driven by metabolic reprogramming that induces aberrant epigenetic modifications to further stimulate glycolysis, resulting in a vicious cycle to exacerbate tumorigenesis.

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IGFBP2 driven glioma progression is prevented by blocking a clinically significant network of integrin, ILK, and NK-kB

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.

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