Radiation-Induced Cellular Plasticity Primes Glioblastoma for Forskolin-Mediated Differentiation [bulk RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1204340 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31856342_1.fastq.gz | Fastqsanger.gz | |||
| SRR31856342_2.fastq.gz | Fastqsanger.gz | |||
| SRR31856343_1.fastq.gz | Fastqsanger.gz | |||
| SRR31856343_2.fastq.gz | Fastqsanger.gz | |||
| SRR31856344_1.fastq.gz | Fastqsanger.gz |
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Project description:Radiation-Induced Cellular Plasticity Primes Glioblastoma for Forskolin-Mediated Differentiation [Day21]
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Project description:Radiation-Induced Cellular Plasticity Primes Glioblastoma for Forskolin-Mediated Differentiation [Day 5]
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Project description:Glioblastoma is the deadliest brain cancer in adults and all patients succumb to the tumor. While surgery followed by chemo-radiotherapy delays disease progression, these treatments do not lead to tumor control and targeted therapies or biologics have failed to further improve survival. Utilizing a transient radiation-induced state of multipotency, we used the adenylcyclase activator forskolin to alter the fate of irradiated glioma cells. The effects of the combined treatment on neuronal marker expression, cell cycle distribution and proliferation were studied. Gene expression profiling was conducted using bulk RNA-seq. Changes in cell populations were investigated using single cell RNA-seq. Effects on glioma stem cells were studied in extreme limiting dilution assays and the effects on median survival were studied in both syngeneic and PDOX mouse models of glioblastoma. The combined treatment induced the expression of neuronal markers in glioma cells, reduced proliferation and led to a distinct gene expression profile. scRNA-seq revealed that the combined treatment forced glioma cells into a microglia- and neuron-like phenotype. In vivo, this treatment led to a loss of glioma stem cells and prolonged median survival. Collectively, our data suggest that revisiting a differentiation therapy with forskolin in combination with radiation could lead to clinical benefit.
2024-12-30 | GSE285544 | GEO
Project description:Glioblastoma is the deadliest brain cancer in adults and all patients succumb to the tumor. While surgery followed by chemo-radiotherapy delays disease progression, these treatments do not lead to tumor control and targeted therapies or biologics have failed to further improve survival. Utilizing a transient radiation-induced state of multipotency, we used the adenylcyclase activator forskolin to alter the fate of irradiated glioma cells. The effects of the combined treatment on neuronal marker expression, cell cycle distribution and proliferation were studied. Gene expression profiling was conducted using bulk RNA-seq. Changes in cell populations were investigated using single cell RNA-seq. Effects on glioma stem cells were studied in extreme limiting dilution assays and the effects on median survival were studied in both syngeneic and PDOX mouse models of glioblastoma. The combined treatment induced the expression of neuronal markers in glioma cells, reduced proliferation and led to a distinct gene expression profile. scRNA-seq revealed that the combined treatment forced glioma cells into a microglia- and neuron-like phenotype. In vivo, this treatment led to a loss of glioma stem cells and prolonged median survival. Collectively, our data suggest that revisiting a differentiation therapy with forskolin in combination with radiation could lead to clinical benefit.
2024-12-30 | GSE285543 | GEO
Project description:Glioblastoma is the deadliest brain cancer in adults and all patients succumb to the tumor. While surgery followed by chemo-radiotherapy delays disease progression, these treatments do not lead to tumor control and targeted therapies or biologics have failed to further improve survival. Utilizing a transient radiation-induced state of multipotency, we used the adenylcyclase activator forskolin to alter the fate of irradiated glioma cells. The effects of the combined treatment on neuronal marker expression, cell cycle distribution and proliferation were studied. Gene expression profiling was conducted using bulk RNA-seq. Changes in cell populations were investigated using single cell RNA-seq. Effects on glioma stem cells were studied in extreme limiting dilution assays and the effects on median survival were studied in both syngeneic and PDOX mouse models of glioblastoma. The combined treatment induced the expression of neuronal markers in glioma cells, reduced proliferation and led to a distinct gene expression profile. scRNA-seq revealed that the combined treatment forced glioma cells into a microglia- and neuron-like phenotype. In vivo, this treatment led to a loss of glioma stem cells and prolonged median survival. Collectively, our data suggest that revisiting a differentiation therapy with forskolin in combination with radiation could lead to clinical benefit.
2024-12-30 | GSE285545 | GEO
Project description:Glioblastoma (GBM) is the deadliest brain cancer in adults, and all patients succumb to the tumor. While surgery followed by chemoradiotherapy delays disease progression, these treatments do not lead to tumor control, and targeted therapies or biologics have failed to further improve survival. Utilizing a transient radiation-induced state of multipotency, we used the adenylcyclase activator forskolin to alter the fate of irradiated glioma cells. The effects of the combined treatment on neuronal marker expression, cell cycle distribution, and proliferation were studied. Gene expression profiling was conducted using bulk RNA-seq. Changes in cell populations were investigated using single-cell RNA-seq. Effects on glioma stem cells (GSCs) were studied in extreme limiting dilution assays, and the effects on median survival were studied in both syngeneic and PDOX mouse models of GBM. The combined treatment induced the expression of neuronal markers in glioma cells, reduced proliferation, and led to a distinct gene expression profile. scRNA-seq revealed that the combined treatment forced glioma cells into a microglia- and neuron-like phenotype. In vivo, this treatment led to a loss of GSCs and prolonged median survival. Collectively, our data suggest that revisiting a differentiation therapy with forskolin in combination with radiation could lead to clinical benefit.
| S-EPMC11892679 | biostudies-literature
Project description:SUMMARY Despite numerous genome-wide association studies involving glioblastoma (GBM), few therapeutic targets have been identified for this disease. Using patient derived glioma sphere cultures (GSCs), we have found that a subset of the proneural (PN) GSCs undergo transition to a mesenchymal (MES) state in a TNFa/NFkB dependent manner with an associated enrichment of CD44 sub-populations and radio-resistant phenotypes. To the contrary, MES GSCs exhibit constitutive NFkB activation, CD44 enrichment and radio-resistance. Patients whose tumors exhibit a higher MES metagene, increased expression of CD44, or activated NFkB were associated with poor radiation response and shorter survival. Our results indicate that NFkB activation mediated MES differentiation and radiation resistance presents an attractive therapeutic target for GBM. SIGNIFICANCE In this study, we show plasticity between the proneural (PN) and mesenchymal (MES) transcriptome signatures observed in glioblastoma (GBM). Specifically, we show that PN glioma sphere cultures (GSCs) can be induced to a MES state with an associated enrichment of CD44 expressing cells and a gain of radio-resistance, which we implicate as NFkB- dependent. Newly diagnosed GBM samples show a direct correlation between radiation response, higher MES metagene, CD44 expression, and NFkB activation. This correlation is also observed in the subset of GBM samples that do not exhibit IDH1 mutation, a favorable prognostic marker. Our results uncover a previously unknown link between subtype plasticity that is regulated by NFkB. Inhibition of NFkB activation can directly impact radio-resistance and presents an attractive therapeutic target for GBM. 4 treatments
2013-08-15 | E-GEOD-49162 | biostudies-arrayexpress
Project description:SUMMARY Despite numerous genome-wide association studies involving glioblastoma (GBM), few therapeutic targets have been identified for this disease. Using patient derived glioma sphere cultures (GSCs), we have found that a subset of the proneural (PN) GSCs undergo transition to a mesenchymal (MES) state in a TNFa/NFkB dependent manner with an associated enrichment of CD44 sub-populations and radio-resistant phenotypes. To the contrary, MES GSCs exhibit constitutive NFkB activation, CD44 enrichment and radio-resistance. Patients whose tumors exhibit a higher MES metagene, increased expression of CD44, or activated NFkB were associated with poor radiation response and shorter survival. Our results indicate that NFkB activation mediated MES differentiation and radiation resistance presents an attractive therapeutic target for GBM. SIGNIFICANCE In this study, we show plasticity between the proneural (PN) and mesenchymal (MES) transcriptome signatures observed in glioblastoma (GBM). Specifically, we show that PN glioma sphere cultures (GSCs) can be induced to a MES state with an associated enrichment of CD44 expressing cells and a gain of radio-resistance, which we implicate as NFkB- dependent. Newly diagnosed GBM samples show a direct correlation between radiation response, higher MES metagene, CD44 expression, and NFkB activation. This correlation is also observed in the subset of GBM samples that do not exhibit IDH1 mutation, a favorable prognostic marker. Our results uncover a previously unknown link between subtype plasticity that is regulated by NFkB. Inhibition of NFkB activation can directly impact radio-resistance and presents an attractive therapeutic target for GBM. Gene expression data for 17 isolated Glioma Stem Cells
2013-08-15 | E-GEOD-49161 | biostudies-arrayexpress
Project description:Background: Glioblastoma (GBM) displays remarkable cell state plasticity, a major contributor to therapeutic resistance and tumor progression. While epigenetic mechanisms play a central role in driving this plasticity, the key regulators remain poorly understood, and developing effective therapeutic strategies targeting them has been challenging. Methods: We investigated the role of BRD2, a key regulator of NF-κB mediated mesenchymal (MES) transition, using GBM patient-derived xenograft (PDX) cell lines, CRISPR-mediated knock-in/knockout approaches, RNA-seq, and in vitro and in vivo modeling. BET inhibitors were employed to target MES gene expression and sensitize GBM to radiation therapy. Results: We found that PTEN loss induces RelA chromatin localization and acetylation-mediated recruitment of BRD2 to the MES gene promoters. BRD2 binding is essential for maintaining MES gene expression and phenotype. Genetic ablation or loss-of-function mutation of BRD2 bromodomains reverses MES transition, enhances radiation sensitivity, and improves survival in orthotopic xenograft models. Additionally, treatment with a brain-penetrant BD2-selective inhibitor suppresses the MES phenotype and increases radiation sensitivity of GBM stem cells in vitro. Conclusion: Our study identifies BRD2 as a key mediator of MES transition in GBM, with its bromodomains playing a crucial role in driving cell state plasticity. Targeting BRD2 with BD2-selective inhibitors offers a promising therapeutic strategy to overcome radiation resistance and improve outcomes for GBM patients.
2025-11-17 | GSE304029 | GEO
Project description:Glioblastoma is the deadliest brain tumor in adults and the standard-of-care consists of surgery followed by radiation and treatment with temozolomide. Overall survival times for patients suffering from glioblastoma are unacceptably low indicating an unmet need for novel treatment options. Using patient-derived glioblastoma lines and mouse models of glioblastoma we tested the effect of radiation and the dopamine receptor antagonist on glioblastoma self-renewal in vitro and survival in vivo. A possible resistance mechanism was investigated using RNA-Sequencing. Treatment of glioma cells with the dopamine receptor antagonist quetiapine reduced glioma cell self-renewal in vitro and combined treatment of mice with quetiapine and radiation prolonged the survival of glioma-bearing animals. The combined treatment induced the expression of genes involved in cholesterol biosynthesis. This rendered the tumors vulnerable to simultaneous treatment with atorvastatin and further significantly prolonged the survival of the animals. Our results indicate promising therapeutic efficacy with the triple combination of quetiapine, atorvastatin and radiation treatment against glioblastoma without increasing the toxicity of radiation. With both drugs readily available for clinical use our study could be rapidly translated into a clinical trial.
2021-01-28 | GSE165624 | GEO