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Glioblastoma Stem Cells Reprogram Chromatin In Vivo To Generate Selective Therapeutic Dependencies

ABSTRACT: Glioblastoma Stem Cells Reprogram Chromatin In Vivo To Generate Selective Therapeutic Dependencies

PROVIDER: PRJNA771531 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16352126_1.fastq.gz	Fastqsanger.gz
	SRR16352126_2.fastq.gz	Fastqsanger.gz
	SRR16352127_1.fastq.gz	Fastqsanger.gz
	SRR16352127_2.fastq.gz	Fastqsanger.gz
	SRR16352128_1.fastq.gz	Fastqsanger.gz

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Glioblastoma Stem Cells Reprogram Chromatin In Vivo To Generate Selective Therapeutic Dependencies [RNA-Seq]

Project description:Glioblastoma Stem Cells Reprogram Chromatin In Vivo To Generate Selective Therapeutic Dependencies [RNA-Seq]

| PRJNA771533 | ENA

Glioblastoma Stem Cells Reprogram Chromatin In Vivo To Generate Selective Therapeutic Dependencies [ChIP-Seq]

Project description:Glioblastoma Stem Cells Reprogram Chromatin In Vivo To Generate Selective Therapeutic Dependencies [ChIP-Seq]

| PRJNA771534 | ENA

Glioblastoma Stem Cells Reprogram Chromatin In Vivo To Generate Selective Therapeutic Dependencies [RNA-Seq]

Project description:Glioblastomas are universally fatal cancers that contain self-renewing glioblastoma stem cells (GSCs) that initiate tumors. Traditional anti-cancer drug discovery based on in vitro cultures tends to identify targets with poor therapeutic index and fails to accurately model the effects of the tumor microenvironment. Here, leveraging in vivo genetic screening, we identified the H3K4me3 regulator DPY30 as an in vivo-specific glioblastoma dependency. Based on the hypothesis that in vivo epigenetic regulation may define critical GSC dependencies, we interrogated active chromatin landscapes of GSCs derived from intracranial xenografts and cell culture through Histone H3 lysine 4 trimethylation (H3K4me3) chromatin immunoprecipitation and transcriptome analysis. Intracranial-specific genes marked by H3K4me3 included FOS, NFkB, and phosphodiesterase family members. In intracranial tumors, DPY30 regulated angiogenesis and hypoxia pathways in an H3K4me3-dependent manner, but was dispensable in cultured GSCs. PDE4B was a key downstream effector of DPY30; the PDE4 inhibitor, rolipram, preferentially targeted DPY30-expressing cells and impaired in vivo glioblastoma growth without affecting cultured tumor cells. Collectively, DPY30 selectively regulates H3K4me3 modification on genes critical to support angiogenesis and tumor growth in vivo, laying the foundation for the DPY30-PDE4B axis as a specific and novel therapeutic target in glioblastoma with a broad therapeutic index.

2021-10-17 | GSE185955 | GEO

Glioblastoma Stem Cells Reprogram Chromatin In Vivo To Generate Selective Therapeutic Dependencies [ChIP-Seq]

2021-10-17 | GSE185954 | GEO

Glioblastoma Stem Cells Reprogram Chromatin In Vivo To Generate Selective Therapeutic Dependencies

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

2021-10-17 | GSE185956 | GEO

Mapping the landscape of genetic dependencies in chordoma

Project description:Identifying the spectrum of genes required for cancer cell survival can reveal essential cancer circuitry and therapeutic targets, but such a map remains incomplete for many cancer types. We apply genome-scale CRISPR-Cas9 loss-of-function screens to map the landscape of selectively essential genes in chordoma, a bone cancer with few validated targets. This approach confirms a known chordoma dependency, TBXT (T; brachyury), and identifies a range of additional dependencies, including PTPN11, ADAR, PRKRA, LUC7L2, SRRM2, SLC2A1, SLC7A5, FANCM, and THAP1. CDK6, SOX9, and EGFR, genes previously implicated in chordoma biology, are also recovered. We find genomic and transcriptomic features that predict specific dependencies, including interferon-stimulated gene expression, which correlates with ADAR dependence and is elevated in chordoma. Validating the therapeutic relevance of dependencies, small-molecule inhibitors of SHP2, encoded by PTPN11, have potent preclinical efficacy against chordoma. Our results generate an emerging map of chordoma dependencies to enable biological and therapeutic hypotheses.

2023-03-09 | GSE226734 | GEO

Discovery and Characterization of Super-Enhancer Associated Dependencies in Diffuse Large B-Cell Lymphoma

Project description:Diffuse Large B-Cell Lymphoma (DLBCL) is a biologically heterogeneous and clinically aggressive disease. Here, we explore the role of BET bromodomain proteins in DLBCL, using integrative chemical genetics and functional epigenomics. We observe highly asymmetric loading of BRD4 at enhancers, with approximately 33% of all BRD4 localizing to enhancers at 1.6% of occupied genes. These super-enhancers prove particularly sensitive to bromodomain inhibition, explaining the selective effect of BET inhibitors on oncogenic and lineage-specific transcriptional circuits. Functional study of genes marked by super-enhancers identifies DLBCLs dependent on OCA-B and suggests a strategy for discovering unrecognized cancer dependencies. Translational studies performed on a comprehensive panel of DLBCLs establish a therapeutic rationale for evaluating BET inhibitors in this disease. ChIP-Seq for various transcription factors and histone modifications in diffuse large B-cell lymphoma cells

2013-12-10 | E-GEOD-46663 | biostudies-arrayexpress

Defining the therapeutic selective dependencies for distinct subtypes of PI3K pathway-altered prostate cancers.

Project description:Previous studies have suggested that PTEN loss is associated with p110β signaling dependency, leading to the clinical development of p110β-selective inhibitors. Here we use a panel pre-clinical models to reveal that PI3K isoform dependency is not governed by loss of PTEN and is impacted by feedback inhibition and concurrent PIK3CA/PIK3CB alterations. Furthermore, while pan-PI3K inhibition in PTEN-deficient tumors is efficacious, upregulation of Insulin Like Growth Factor 1 Receptor (IGF1R) promotes resistance. Importantly, we show that this resistance can be overcome through targeting AKT and we find that AKT inhibitors are superior to pan-PI3K inhibition in the context of PTEN loss. However, in the presence of wild-type PTEN and PIK3CA-activating mutations, p110α-dependent signaling is dominant and selectively inhibiting p110α is therapeutically superior to AKT inhibition. These discoveries reveal a more nuanced understanding of PI3K isoform dependency and unveil novel strategies to selectively target PI3K signaling nodes in a context-specific manner.

| S-EPMC8379232 | biostudies-literature

lncRNA dependencies in acute myeloid leukemia

Project description:lncRNA dependencies in acute myeloid leukemia

| PRJNA354371 | ENA

Targeting transcriptional dependencies in cancer using a covalent CDK7 inhibitor (ChIP-Seq)

Project description:Cyclin-dependent kinase 7 (CDK7) plays a critical role in the general regulation of RNA polymerase II-mediated transcription. However, the absence of selective CDK7 inhibitors has hindered the ability to investigate the consequences of acute and prolonged inhibition of CDK7 under normal and pathological conditions. Here we present the discovery and characterization of the first covalent CDK7 inhibitor, CDK7-IN-1, that has the unprecedented ability to target a unique cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7 amongst the 20 known CDKs. Cancer cell line profiling indicates that a subset of cancer cell lines, including T-cell acute lymphoblastic leukemia (T-ALL), exhibit 100-fold greater sensitivity to CDK7-IN-1 over other tumor and normal cell lines. Genome-wide expression analysis in Jurkat T-ALL indicates that CDK7-IN-1 disproportionally affects RUNX1 as well as other components of the TAL1 transcriptional network and its targets, downregulating key regulators of transcription and apoptosis critical for the T-ALL state. These oncogenes are encoded by short-lived mRNA transcripts, are associated with super-enhancers, and exhibit a strong dependency on continuous transcription for sustained expression. Therefore, pharmacological modulation of CDK7 kinase activity may define a method for the identification and treatment of tumor types exhibiting extreme dependencies on transcription for maintenance of the oncogenic state. Jurkat cells were treated with various drugs including a covalent inhibitor of CDK7 (CDK7-IN-1), a reversible inhibitor of CDK7 (CDK7-IN-1), Flavopiridol, Actinomycin D, and DMSO controls. Replicates are annotated.

2013-12-23 | E-GEOD-50622 | biostudies-arrayexpress

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