Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Multi-omics approaches reveal that Diffuse Midline Gliomas are susceptible to replication stress therapy and cholesterol biosynthesis inhibition [Repli-seq]

ABSTRACT: The fatal Diffuse Midline Gliomas (DMG) are characterized by an undruggable H3K27M mutation in H3.1 or H3.3. K27M impairs normal development by stalling of differentiation. As replication timing influences gene expression, cell fate, and cellular response to therapeutics, we undertook a multi-omics approach (Repli-seq, cell cycle RNA-seq, single cell RNA-seq) in DMG cells (H3.1K27M and H3.3K27M subgroups) and tumors in comparison to normal brain to gain an appreciation for targetable pathways in DMG. DMG cells presented differential replication timing in each subgroup, which, in turn, correlated with significant differential gene expression including the cholesterol biosynthesis pathway. Consistent with these findings, DMG tumors presented high replication stress and cholesterol biosynthesis pathway signatures. Moreover, DMG cells were specifically vulnerable to an inhibitor of the cholesterol pathway and to a replication stress therapy, singly and in combination. In conclusion, this combinatorial genomics approach revealed insights into therapeutic opportunities for this incurable disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE268775 | GEO | 2024/11/20

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Multi-omics approaches reveal that Diffuse Midline Gliomas are susceptible to replication stress therapy and cholesterol biosynthesis inhibition [RNA-seq]

Project description:The fatal Diffuse Midline Gliomas (DMG) are characterized by an undruggable H3K27M mutation in H3.1 or H3.3. K27M impairs normal development by stalling of differentiation. As replication timing influences gene expression, cell fate, and cellular response to therapeutics, we undertook a multi-omics approach (Repli-seq, cell cycle RNA-seq, single cell RNA-seq) in DMG cells (H3.1K27M and H3.3K27M subgroups) and tumors in comparison to normal brain to gain an appreciation for targetable pathways in DMG. DMG cells presented differential replication timing in each subgroup, which, in turn, correlated with significant differential gene expression including the cholesterol biosynthesis pathway. Consistent with these findings, DMG tumors presented high replication stress and cholesterol biosynthesis pathway signatures. Moreover, DMG cells were specifically vulnerable to an inhibitor of the cholesterol pathway and to a replication stress therapy, singly and in combination. In conclusion, this combinatorial genomics approach revealed insights into therapeutic opportunities for this incurable disease.

2024-11-20 | GSE268776 | GEO

CHD2 Regulates Neuron-glioma Interactions in Pediatric Glioma

Project description:High-grade gliomas (HGG) are deadly diseases for both adult and pediatric patients. Recently, it has been shown that neuronal activity promotes the progression of multiple subgroups of HGG. However, epigenetic mechanisms that govern this process remain elusive. Here we report that the chromatin remodeler CHD2 regulates neuron-glioma interactions in diffuse midline glioma (DMG) characterized by onco-histone H3.1K27M. Depletion of CHD2 in H3.1K27M DMG cells compromises cell viability and neuron-to-glioma synaptic connections in vitro, neuron-induced proliferation of H3.1K27M HGG DMG cells in vitro and in vivo, activity-dependent calcium transients in vivo, and extends the survival of H3.1K27M DMG-bearing mice. Mechanistically, CHD2 coordinates with the transcription factor FOSL1 to control the expression of axon-guidance and synaptic genes in H3.1K27M DMG cells. Together, our study reveals a mechanism whereby CHD2 controls the intrinsic gene program of the H3.1K27M DMG subtype, which in turn regulates the tumor growth-promoting interactions of glioma cells with neurons.

2024-05-09 | GSE211074 | GEO

Integrated analyses reveal two molecularly and clinically distinct subtypes of H3 K27M-mutant diffuse midline gliomas with prognostic significance

Project description:We identified two subgroups of diffuse midline gliomas (DMGs) with unsupervised hierarchical cluster analyses of DNA methylation data from 149 DMGs derived from different localisations: DMG-A and DMG-B. The two epigenetic DMG-subtypes have different characteristics: DMG-A are enriched for cases with MAPK-signalling-pathway associated mutations, a methylated MGMT-promoter, medullary localisation and adult age, while DMG-B are enriched for cases with TP53-mutations, PDGFRA-amplifications, pontine localisation and paediatric patients. DMG-A have a significantly better overall survival compared to DMG-B (p < 0.001). This effect on survival is larger than that of all other parameters tested, and all other parameters are dependent on the cluster attribution. Hence, the subtype attribution based on two methylation clusters is best suited to predict survival as it integrates different molecular and clinical parameters.

2024-09-02 | GSE270993 | GEO

Histone H3 wild-type DIPG/DMG overexpressing EZHIP extend the spectrum diffuse midline gliomas with PRC2 inhibition beyond H3-K27M mutation

Project description:Characterisation of a new subgroup of DMG lacking H3-K27M mutation that is defined by H3K27me3 loss and EZHIP overexpression that can be detected by IHC. These tumors are distinct from EZHIP-positive posterior fossa ependymomas and are associated with a dismal prognosis. We propose that these EZHIP/H3-WT tumors need to be considered similar to canonical DIPG/DMG, thus extending the spectrum of DMG with PRC2 inhibition beyond H3-K27M mutation

2020-03-20 | E-MTAB-8888 | biostudies-arrayexpress

Venetoclax cooperates with ionizing radiation to attenuate Diffuse Midline Glioma tumor growth

Project description:This article highlights the radiation induced cytotoxic effect of the BCL2 inhibitor, venetoclax, in diffuse midline gliomas (DMG). 1. RNA-seq: We performed bulk RNA sequencing of DMG cells exposed to 6Gy radiation and found the genes upregulated after radiation compared to unirradiated controls. 2. DNA Repair shRNA screen: We also performed a DNA Repair shRNA screen and identified the genes which are responsible for radioresistance in DMG.

2022-03-23 | GSE198979 | GEO

Preclinical Optimization of the PI3K/Akt inhibitor Paxalisib for the Treatment of Diffuse Midline Glioma

Project description:Diffuse midline glioma (DMG) is a uniformly fatal pediatric, adolescent, and young adult cancer diagnosed in the midline structures of the brain. PI3K/Akt signaling is an overarching contributor to the poor outcomes of DMG patients due to their dependance on insulin and recurring mutations and amplifications in PI3K/Akt genes. Paxalisib (GDC-0084) is a potent PI3K/Akt inhibitor developed to penetrate the brain’s protective blood-brain barrier (BBB). We performed paxalisib regimen optimization by assessment of blood glucose levels, analysis in vivo pharmacokinetics/pharmacodynamics properties, and employed DMG patient derived xenograft (PDX) mouse models to determine preclinical efficacy. To identify novel combination strategies, we conducted high-resolution quantitative phosphoproteomics of DMG cells treated with paxalisib. Elevated blood glucose levels promoting hyperglycemia was seen in mice using paxalisib 10 mg/kg/day (~mouse equivalent human maximum tolerated dose- NCT03696355). Whereas 5 mg/kg/day, or 5mg/kg/b.i.d. (twice daily) non-significantly increased blood glucose levels compared to controls. Pharmacokinetic analysis of mouse tissues showed 5 mg/kg/b.i.d. increased paxalisib acumination in the brainstem, suppressing PI3K/Akt signaling to significantly extend the survival of DMG PDX models compared to all other regimens; a survival benefit amplified when combined with the anti-glycemic therapy metformin. Phosphoproteomic profiling identified increased Protein kinase C (PKC) signaling following paxalisib treatment. The combination of paxalisib and enzastaurin (PKC inhibitor) synergistically extended the survival of PDX models. Our optimized dosing regimen increased the preclinical benefits of paxalisib, with the combination of paxalisib with metformin, or paxalisib with enzastaurin, heralding rationally designed combination strategies for the treatment of DMG

2024-02-20 | PXD036114 | Pride

Defining tumor-associated vascular heterogeneity in pediatric high-grade and diffuse midline gliomas

Project description:The blood-brain barrier (BBB) plays important roles in brain tumor pathogenesis and treatment response, yet our understanding of its function and heterogeneity within or across brain tumor types remains poorly characterized. Here we analyze the neurovascular unit (NVU) of pediatric high-grade glioma (pHGG) and diffuse midline glioma (DMG) using patient derived xenografts and natively forming glioma mouse models. We show tumor-associated vascular differences between these glioma subtypes, and parallels between PDX and mouse model systems, with DMG models maintaining a more normal vascular architecture, BBB function and endothelial transcriptional program relative to pHGG models. Unlike prior work in angiogenic brain tumors, we find that expression of secreted Wnt antagonists do not alter the tumor-associated vascular phenotype in DMG tumor models. Together, these findings highlight vascular heterogeneity between pHGG and DMG and differences in their response to alterations in developmental BBB signals that may participate in driving these pathological differences.

2021-09-01 | GSE179372 | GEO

The oncolytic adenovirus Delta-24-RGD in combination with ONC201 induces a potent antitumor response in pediatric high-grade and diffuse midline glioma models [RNA-seqII]

Project description:Background: Pediatric high-grade gliomas (pHGGs), including diffuse midline gliomas (DMGs), are aggressive pediatric tumors with one of the poorest prognoses. Delta-24-RGD and ONC201 have shown promising efficacy as single agents for these tumors. However, the combination of both agents has not been evaluated. Methods: The production of functional viruses was assessed by immunoblotting and replication assays. The antitumor effect was evaluated in a panel of human and murine pHGG and DMG cell lines. RNAseq, the seahorse stress test, mitochondrial DNA content, and γH2A.X immunofluorescence were used to perform mechanistic studies. Mouse models of both diseases were used to assess the efficacy of the combination in vivo. The tumor immune microenvironment was evaluated using flow cytometry, RNAseq and multiplexed immunofluorescence staining. Results: The Delta-24-RGD/ONC201 combination did not affect the virus replication capability in human pHGG and DMG models in vitro. Cytotoxicity analysis showed that the combination treatment was either synergistic or additive. Mechanistically, the combination treatment increased nuclear DNA damage and maintained the metabolic perturbation and mitochondrial damage caused by each agent alone. Delta-24-RGD/ONC201 cotreatment extended the overall survival of mice implanted with human and murine pHGG and DMG cells, independent of H3 mutation status and location. Finally, combination treatment in murine DMG models revealed a reshaping of the tumor microenvironment to a proinflammatory phenotype. Conclusions: The Delta-24-RGD/ONC201 combination improved the efficacy compared to each agent alone in in vitro and in vivo models by potentiating nuclear DNA damage and in turn improving the antitumor (immune) response to each agent alone.

2024-05-09 | GSE255971 | GEO

ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma

Project description:Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of all childhood cancers. Palliative radiotherapy is the only proven life-prolonging treatment, with patient survival 9-11 months. ONC201 shows preclinical and emerging clinical efficacy in DIPG. Currently, little is known about the mechanisms of sensitivity/resistance of DIPGs to ONC201, or whether recurring genomic features influence response. Using a systems-biological approach, we show ONC201 elicits potent agonism of the mitochondrial protease, CLPP, driving proteolysis of electron transport chain (ETC) and tricarboxylic acid (TCA) cycle proteins. DIPGs harboring TP53-mutations show reduced sensitivity to ONC201. Molecular mechanisms identify metabolic adaptation and resistance to ONC201 regulated by redox-activated PI3K/Akt signaling, counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib, in both wt-TP53 and TP53-mutant DIPGs. The discoveries described within, coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib inform the DIPG/DMG phase II combination clinical trial NCT05009992.

2023-05-25 | PXD036245 | Pride

Mutations within FGFR1 and BRAF indicate superior outcome in diffuse midline gliomas, H3F3A K27M mutant

Project description:Diffuse midline glioma (DMG) is a devastating disease that is defined by its localization, by the diffuse growth of astrocytic tumor cells, and by K27M mutations within Histone H3 proteins. In a large series of such tumor samples (n=83), we show here that 12 % of these cases (n=10) harbor concomitant hotspot mutations within FGFR1 or BRAF. Respective cases were all located in midline structures and matched with reference cases of DMG using global DNA methylation profiling. TP53 mutations were significantly more frequent in BRAF/FGFR1 wild type cases. Presence of hotspot mutations within FGFR1 or BRAF was associated with a significantly better overall survival, which was independent of the patients’ age and tumor localization. Thus, our results establish the relevance of FGFR1 or BRAF mutations in DMG as a prognostic marker and open new targeted therapy options in this subgroup of DMG.

2020-12-08 | GSE161944 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data