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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE185954 | GEO | 2021/10/17

REPOSITORIES: GEO

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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.

2021-10-17 | GSE185955 | GEO

Targeting EYA2 tyrosine phosphatase activity in glioblastoma stem cells induces mitotic catastrophe

Project description:Glioblastoma ranks among the most lethal of primary brain malignancies, with glioblastoma stem cells (GSCs) at the apex of tumor cellular hierarchies. Here, to discover novel therapeutic GSC targets, we interrogated gene expression profiles from GSCs, differentiated glioblastoma cells (DGCs), and neural stem cells (NSCs), revealing EYA2 as preferentially expressed by GSCs. Targeting EYA2 impaired GSC maintenance and induced cell cycle arrest, apoptosis, and loss of self-renewal. EYA2 displayed novel localization to centrosomes in GSCs, and EYA2 tyrosine (Tyr) phosphatase activity was essential for proper mitotic spindle assembly and survival of GSCs. Inhibition of the EYA2 Tyr phosphatase activity, via genetic or pharmacological means, mimicked EYA2 loss in GSCs in vitro and extended the survival of tumor-bearing mice. Supporting the clinical relevance of these findings, EYA2 portends poor patient prognosis in glioblastoma. Collectively, our data indicate that EYA2 phosphatase function plays selective critical roles in the growth and survival of GSCs, potentially offering a high therapeutic index for EYA2 inhibitors.

2021-09-25 | GSE135306 | GEO

Glioma stem cell treatment with MELK-signaling inhibitors

Project description:Glioblastoma multiforme (GBM) is a highly lethal brain tumor. Due to resistance to current therapies, patient prognosis remains poor and development of novel and effective GBM therapy is crucial. Glioma stem cells (GSCs) have gained attention as therapeutic target in GBM due to their relative resistance to current therapies and potent tumor-initiating ability. Recent studies including our own identified that the mitotic kinase, maternal embryonic leucine-zipper kinase (MELK), is highly expressed in GBM tissues, specifically in GSCs, and its expression is inversely correlated with the post-surgical survival period of GBM patients. In addition, patient-derived GSCs depend on MELK for their survival and growth both in vitro and in vivo. Here, we provide evidence that the kinase activity of MELK is essential for the action of MELK in GSCs and vital for GBM growth. We utilized in silico structure-based analysis for protein-compound interaction to predict that a recently identified small molecule, Compound 1 (C1), binds to the kinase-active site of MELK protein and eliminates MELK kinase activity in nanomolar concentrations. When treated with C1, GSCs undergo mitotic arrest and subsequent cellular apoptosis in vitro, a phenotype identical to that observed using MELK shRNA-mediated knockdown. C1 treatment strongly induces tumor cell apoptosis in slice cultures of GBM surgical specimens and attenuates growth of mouse intracranial tumors derived from GSCs in a dose-dependent manner. Lastly, C1 treatment sensitizes GSCs to radiation treatment. Collectively, these data indicate that targeting MELK kinase activity is a promising approach to attenuate GBM growth by eliminating GSCs in tumors. Microarray-based expression analysis of glioma stem cells treated with MELK-signaling inhibitors

2013-08-28 | E-GEOD-50227 | biostudies-arrayexpress

Identification and molecular characterization of distinct glioblastoma cancer stem cell populations

Project description:Malignant glioblastoma (GBM) is a highly aggressive brain tumor with a dismal prognosis and limited therapeutic options. Genomic profiling of GBM samples in the TCGA database has identified four molecular subtypes (Proneural, Neural, Classical and Mesenchymal), which may arise from different glioblastoma stem-like cell (GSC) populations. In the present study, we identify two GSC populations that produce GBM tumors by subcutaneous and intracranial injection with identical histological features. Gene expression analysis revealed that xenografts of GSCs grown as spheroid cultures had a Classical molecular subtype similar to that of bulk tumor cells. In contrast xenografts of GSCs grown as adherent cultures on laminin-coated plates expressed a Mesenchymal gene signature. Adherent GSC-derived xenografts had high STAT3 and ANGPTL4 expression as well as enrichment for stem cell markers, transcriptional networks and pro-angiogenic markers characteristic of the Mesenchymal subtype. Examination of clinical samples from GBM patients showed that STAT3 expression was directly correlated with ANGPTL4 expression, and that increased expression of these genes correlated with poor patient survival and performance. A pharmacological STAT3 inhibitor abrogated STAT3 binding to the ANGPTL4 promoter and exhibited anticancer activity in vivo. Taken together, we identified two distinct GSC populations that produce histologically identical tumors but with very different gene expression patterns, and a STAT3/ ANGPTL4 pathway in glioblastoma that may serve as a target for therapeutic intervention. 2 samples of each variable were analyzed. Cells were cultured under normal adherent conditon (Bulk tumor cells), non-adherent plates with stem cell medium (Sp-GSC) or laminin-coated plates with stem cell medium (Ad-GSC). Xenografts were generated in NSG mice by subcutaneous inoculation.

2015-07-01 | E-GEOD-65576 | biostudies-arrayexpress

The RNA m6A reader YTHDF2 maintains oncogene expression and is a targetable dependency in glioblastoma stem cells [m6A RIP-seq]

Project description:Glioblastoma is a universally lethal cancer driven by glioblastoma stem cells (GSCs). Here, we interrogated N6-methyladenosine (m6A) mRNA modifications in GSCs by methyl RNA-immunoprecipitation followed by sequencing (meRIP-seq) and transcriptome analysis, finding transcripts marked by m6A often upregulated. Interrogating m6A regulators, GSCs displayed preferential expression as well as in vitro and in vivo dependency of the m6A reader, YTHDF2, in contrast to normal neural stem cells (NSCs). While YTHDF2 has been reported to destabilize mRNAs, YTHDF2 stabilized the oncogene transcripts, MYC and VEGFA, in GSCs in an m6A-dependent manner. We identified IGFBP3 as a downstream effector of the YTHDF2-MYC axis in GSCs and IGF1/IGF1R inhibitor, Linsitinib, as preferentially targeting YTHDF2-expressing cells, inhibiting the viability of GSCs without affecting NSCs and impairing in vivo glioblastoma growth. Thus, YTHDF2 links RNA epitranscriptomic modifications and GSC growth, laying the foundation for the YTHDF2-MYC-IGFBP3 axis as a specific and novel therapeutic target in glioblastoma.

2020-09-29 | GSE158741 | GEO

The RNA m6A reader YTHDF2 maintains oncogene expression and is a targetable dependency in glioblastoma stem cells [RNA-seq]

2020-09-29 | GSE158740 | GEO

YTHDF2 iCLIP in glioblastoma stem cells

2020-09-29 | GSE158020 | GEO

Identification and molecular characterization of distinct glioblastoma cancer stem cell populations

2015-07-01 | GSE65576 | GEO

ARS2/MAGL signaling in glioblastoma stem cells promotes self-renewal and M2-like polarization of tumor-associated macrophages I

Project description:The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E2 (PGE2), which stimulates β-catenin activation of GSC and M2-like TAM polarization. Specific knockdown of ARS2 or MAGL significantly suppressed self-renewal and tumor growth, and increased survival in a mouse intracranial xenograft model of GSCs. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE2 production. The M2-like signature is enriched in mesenchymal subtype and predicted poor survival in GBM patients. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients.

2020-05-16 | GSE150630 | GEO

Microarray analysis of differentiation of human glioblastoma stem cells

Project description:Glioblastoma multiforme is one of the most devastating cancers and presents unique challenges to therapy due to its aggressive behaviour. Cancer stem cells have been described to be the only cell population with tumorogenic capacity in glioblastoma. Therefore, effective therapeutic strategies targeting these cells may be beneficial. We have established different cultures of glioblastoma stem cells (GSCs) derived from surgical specimens and found that, after induction of differentiation, NFκB was activated, which allows intermediate tumor precursor cells to remain cycling. We also showed that blockade of NFκB signaling in differentiating GSCs by different genetic strategies or treatment with small molecule inhibitors, promoted replication arrest, progression to a mature phenotype, mainly neuronal cells, and senescence. This effect was partly mediated by downregulation of the NFκB target gene cyclin D1. Furthermore, intravenous treatment of immunodeficient mice bearing human GSC-derived tumors with a novel small-molecule inhibitor of the NFκB pathway induced senescence of tumor cells but no ultraestructural alterations of the brain parenchymal cells were detected. These findings reveal that activation of NFκB may keep differentiating GSCs from acquiring a mature postmitotic phenotype, thus allowing cell proliferation, and support the rationale for therapeutic strategies aimed at promoting premature senescence in GSCs undergoing differentiation. Gene expression in differentiated cells relative to stem cells in three different glioblastoma cultures

2011-03-01 | E-GEOD-20736 | biostudies-arrayexpress

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