Targeting the non-coding genome and temozolomide signature enables CRISPR-mediated glioma oncolysis
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ABSTRACT:
PROVIDER: PRJNA1023271 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26260907_1.fastq.gz | Fastqsanger.gz | |||
| SRR26260907_2.fastq.gz | Fastqsanger.gz | |||
| SRR26260908_1.fastq.gz | Fastqsanger.gz | |||
| SRR26260908_2.fastq.gz | Fastqsanger.gz | |||
| SRR26260909_1.fastq.gz | Fastqsanger.gz |
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Project description:Glioblastoma (GBM) is the most common lethal primary brain cancer in adults. Despite treatment regimens including surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy, growth of residual tumor leads to therapy resistance and death. At recurrence, a quarter to a third of all gliomas have hypermutated genomes 5, with mutational burdens orders of magnitude greater than in normal tissue. Here, we quantified the mutational landscape progression in a patient’s primary and recurrent GBM, and uncovered Cas9-targetable repeat elements. We show that CRISPR-mediated targeting of highly repetitive loci enables rapid elimination of GBM cells, an approach we term “Genome Shredding”. Importantly, in the patient’s recurrent GBM, we identified unique repeat sequences with TMZ mutational signature and demonstrate that their CRISPR targeting enables cancer-specific cell ablation. “Cancer Shredding” leverages the non-coding genome and therapy-induced mutational signatures for targeted GBM cell depletion and provides an innovative paradigm to develop treatments for hypermutated glioma.
2023-10-05 | GSE244497 | GEO
Project description:Transcriptional profiling of glioma cells comparing control U87(Temozolomide sensitive) cells with U87R(Temozolomide resistant). The U87 cell line was given a low dose of temozolomide in culture media for 3 weeks, resulting in the formation of temozolomide-resistant cells made as U87R.
2023-03-01 | GSE193957 | GEO
Project description:Glioblastoma (GBM) is the most common lethal primary brain cancer in adults. Despite treatment regimens including surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy, growth of residual tumor leads to therapy resistance and death. At recurrence, a quarter to a third of all gliomas have hypermutated genomes, with mutational burdens orders of magnitude greater than in normal tissue. Here, we quantified the mutational landscape progression in a patient's primary and recurrent GBM, and we uncovered Cas9-targetable repeat elements. We show that CRISPR-mediated targeting of highly repetitive loci enables rapid elimination of GBM cells, an approach we term "genome shredding." Importantly, in the patient's recurrent GBM, we identified unique repeat sequences with TMZ mutational signature and demonstrated that their CRISPR targeting enables cancer-specific cell ablation. "Cancer shredding" leverages the non-coding genome and therapy-induced mutational signatures for targeted GBM cell depletion and provides an innovative paradigm to develop treatments for hypermutated glioma.
| S-EPMC10725516 | biostudies-literature
Project description:Acquired resistance of temozolomide (TMZ) is one of the major obstacle of glioblastoma clinical treatment and the mechanism of TMZ resistance is still not very clear. In the presented research we show that deletion of rs16906252-associated MGMT enhancer in MGMT negative glioma cells induced increase sensitivity to temozolomide and combination of RNA-seq and Capture HiC identified several long-range target genes of rs16906252-associated MGMT enhancer. In addition, HiC data shows alterations of chromatin structures in glioma cells survived from high-dosage TMZ treatment and changes of TADs influence rs16906252-associated MGMT enhancer’s long-range regulations of target genes. Our study suggests rs16906252-associated MGMT enhancer regulates glioma cells’ TMZ sensitivity by long-range regulations of several target genes, which is a novel mechanism of regulation of TMZ sensitivity in glioma cells.
2020-04-02 | GSE129476 | GEO
Project description:Temozolomide (TMZ) resistance of glioma cells is currently a critical problem in glioma clinical treatment. In this study, we reveal a bivalent function of a super-enhancer RNA LINC02454 in modulating glioma cell sensitivity to TMZ via regulation of SORBS2 and DDR expression. LINC02454 increased TMZ sensitivity by maintaining 3D chromatin structure and promoting SORBS2 expression, but paradoxically decreased TMZ sensitivity by binding to the DDR1 locus and promoting DDR1 transcription. This study proposes a new regulatory mechanism governing glioma cell sensitivity to TMZ and provides new insights that may improve therapies against glioma.
2024-01-10 | GSE229600 | GEO
Project description:There is little overlap on publicily avaiable gene signatures and it is unclear how relevant these are to glioma biology. MYC is a very dynamically regulated gene, and it's gene signature will vary with respect to cell context. To determine what genes fall within the MYC signature of glioma, we performed ChIP-SEQ upon 4 different glioma PDX with two different MYC antibodies. The overlapping enriched genes will provide context of a MYC signature within the context of glioma.
2022-09-12 | GSE206873 | GEO
Project description:Overexpression of histone deacetylases (HDACs) in cancer commonly causes resistance to genotoxic based therapies. Here we report on the novel mechanism whereby overexpressed class I HDACs increase the resistance of glioblastoma cells to the SN1 methylating agent temozolomide (TMZ). The chemotherapeutic TMZ triggers the activation of the DNA damage response (DDR) in resistant glioma cells, leading to DNA lesion bypass and cellular survival. Mass spectrometry analysis revealed that the catalytic activity of class I HDACs stimulates the expression of the E3 ubiquitin ligase RAD18. Furthermore, the data show that RAD18 is part of the O6-methylguanine-induced DDR as TMZ induces the formation of RAD18 foci at sites of DNA damage. Downregulation of RAD18 by HDAC inhibition prevents glioma cells from activating the DDR upon TMZ exposure. Lastly, RAD18 or O6-methylguanine-DNA methyltransferase (MGMT) overexpression abolishes the sensitization effect of HDAC inhibition on TMZ-exposed glioma cells. Our study describes the mechanism whereby class I HDAC overexpression in glioma cells causes resistance to TMZ treatment. HDACs accomplish this by promoting the bypass of O6-methylguanine DNA lesions via enhancing RAD18 expression. It also provides a treatment option with HDAC inhibition to undermine this mechanism.
2022-04-01 | PXD028683 | Pride
Project description:Purpose: Gut microbiota is associated with the progression of brain tumor. However, the alterations in the gut microbiota during glioma growth and temozolomide (TMZ) therapy remains to be understood. Methods: C57BL/6 male mice were implanted with GL261 glioma cells. TMZ/sodium carboxymethyl cellulose (SCC) was administered by gavage for five consecutive days (from 8 to 12 days after implantation). Fecal samples were collected before (T0) and on days 7 (T1), 14 (T2), and 28 (T3) after implantation. The gut microbiota was analyzed using 16S ribosomal DNA sequencing followed by absolute and relative quantitation analyses. Results: Nineteen genera were altered during glioma progression with the most dramatic changes in Firmicutes and Bacteroidetes phyla. During glioma growth, Lactobacillus abundance decreased at the earlier stage of glioma development (T1), and then gradually increased (T2, T3); Intestinimonas abundance exhibited a persistent increase; Anaerotruncus showed a transient increase and then a subsequent decrease. Twenty genera altered following TMZ treatment. The enrichment of Akkermansia and Bifidobacterium was observed only at the early stage following TMZ treatment (T2), but not at the later stage (T3). Additionally, the decrease of Anaerotruncus was slighter in TMZ group at T3 comparing to the vehicle group. The abundance of Intestinimonas increased constantly during the progression of glioma, but was unaffected by TMZ. Conclusions: Glioma development and progression resulted in altered gut microbiota. TMZ reversed the decrease of Anaerotruncus in glioma at T3, and increased the abundance of Bifidobacterium with no influence on the increase of Intestinimonas. Short-term and long-term effects of TMZ treatment on the bacterial communities may be differential. This study will improve understanding the role of gut microbiota in glioma, and help develop gut microbiota as a potential therapeutic target.
2021-04-28 | GSE171041 | GEO
Project description:Microarray analysis of glioma cell lines : Temozolomide Sensitive vs. Resistant
| PRJNA798609 | ENA