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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 [ChIP-Seq]

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

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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.

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

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

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

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Reprogram glioblastoma (GBM) human cell line into DC

Project description:Reprogram glioblastoma (GBM) human cell line into DC

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Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells

Project description:Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. Here, we explore functional drivers of post-treatment recurrent GBM. By conducting genome-wide CRISPR-Cas9 knockout screens in patient-derived GBM models, we uncover distinct genetic dependencies in recurrent tumor cells absent in their patient-matched primary predecessors, accompanied by increased mutational burden and differential transcript and protein expression. These analyses map a multilayered genetic response to drive tumor recurrence, identifying protein tyrosine phosphatase 4A2 (PTP4A2) as a novel modulator of self-renewal, proliferation and tumorigenicity at GBM recurrence. Genetic perturbation or small molecule inhibition of PTP4A2 activity represses axon guidance activity through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1), exploiting a functional dependency on ROBO signaling. Importantly, engineered anti-ROBO1 single-domain antibodies mimic effects of PTP4A2 inhibition. Since a pan-PTP4A inhibitor was limited by poor penetrance across the blood brain barrier (BBB) in vivo, a second-generation chimeric antigen receptor (CAR)-T cell therapy was engineered against ROBO1 that elicits specific and potent anti-tumor responses in vivo. A single dose of anti-ROBO1 CAR-T cells doubles median survival in patient-derived xenograft (PDX) models of recurrent glioblastoma, and also eradicates tumors in ~50% of mice in PDX models of adult lung-to-brain metastases and pediatric relapsed medulloblastoma. We conclude that functional reprogramming drives tumorigenicity and dependence on a multi-targetable PTP4A-ROBO1 signaling axis at GBM recurrence, with potential in other malignant brain tumors.

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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

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