Identification of Human Pluripotent Stem Cell Derived Astrocytic Progenitors that Correlate with Glioblastoma Subtypes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE226740 | GEO | 2023/03/07
REPOSITORIES: GEO
Similar Datasets
Project description:To investigate the heterogeneity of astrocyte progenitor subtypes present during human astrocyte differentiation that share molecular similarities with tumor initiating stem cells in GBM, we FACS isolated 4 populations of astrocytic progenitor subtypes as identified by the expression of cell surface markers CD51, CD63, and CD71 from three independent iPSC-derived neural progenitor cell lines.
2023-05-31 | GSE226647 | GEO
Project description:Glioblastoma (GBM) is defined by heterogenous and resilient cell populations that closely reflect neurodevelopmental cell types. While it is clear that GBM echoes early and immature cell states, identifying the specific developmental programs disrupted in these tumors has been hindered by a lack of high-resolution trajectories of glial and neuronal lineages. Here, we delineate the course of human astrocyte maturation to uncover discrete developmental stages and attributes mirrored by GBM. We generated a transcriptomic and epigenomic map of human astrocyte maturation using cortical organoids maintained in culture for nearly two years. Through this approach, we chronicled a multi-phase developmental process orchestrated by a series of transcription factor and gene regulatory networks. Our time course of human astrocyte maturation includes a novel and molecularly distinct intermediate period that serves as a lineage commitment checkpoint upstream of mature quiescence. This intermediate stage acts as a site of developmental deviation separating IDH-wildtype neoplastic astrocyte lineage cells from quiescent astrocyte populations. Interestingly, IDH1-mutant tumor astrocyte lineage cells are the exception to this developmental perturbation, where immature properties are suppressed as a result of D2HG oncometabolite exposure. We propose that this defiance is likely a consequence of IDH1mt-associated epigenetic dysregulation and we identified biased DNA hydroxymethylation (5hmC) in maturation genes as a possible mechanism. Together, this study illustrates a novel cellular state aberration in GBM astrocyte lineage cells and presents new developmental targets for experimental and therapeutic exploration.
2024-10-31 | GSE276177 | GEO
Project description:Tumor-initiating cells (TICs) play a critical role in glioblastoma (GBM) maintenance being responsible for its heterogeneity and resistance to standard therapy. A step toward clinical translation includes GBM TIC targeting. Among the molecules tested for GBM treatment, are those targeting epigenetic modifiers. By using patient-derived TICs and xenograft orthotopic models, we identified Lysine-specific histone demethylase 1A (LSD1) as a potentially druggable target in GBM. LSD1-directed therapy by means of the selective, orally bioavailable and brain penetrant inhibitor DDP_38003 effectively impairs growth, stem-like features and tumorigenic potential of GBM TICs. Our findings point to LSD1 as a positive regulator of Activating Transcription Factor 4 (ATF4)-dependent response in all stress conditions arising during tumor growth and therapy. Thus, through the downregulation of either ATF4 and its adaptive genes, LSD1 targeting is likely a promising strategy to hit GBM TICs by counteracting the ATF4-mediated adaptation to stress.
2022-06-02 | PXD021429 | Pride
Project description:Glioblastoma (GBM) is defined by heterogenous and resilient cell populations that closely reflect neurodevelopmental cell types. While it is clear that GBM echoes early and immature cell states, identifying the specific developmental programs disrupted in these tumors has been hindered by a lack of high-resolution trajectories of glial and neuronal lineages. Here, we delineate the course of human astrocyte maturation to uncover discrete developmental stages and attributes mirrored by GBM. We generated a transcriptomic and epigenomic map of human astrocyte maturation using cortical organoids maintained in culture for nearly two years. Through this approach, we chronicled a multi-phase developmental process orchestrated by a series of transcription factor and gene regulatory networks. Our time course of human astrocyte maturation includes a novel and molecularly distinct intermediate period that serves as a lineage commitment checkpoint upstream of mature quiescence. This intermediate stage acts as a site of developmental deviation separating IDH-wildtype neoplastic astrocyte lineage cells from quiescent astrocyte populations. Interestingly, IDH1-mutant tumor astrocyte lineage cells are the exception to this developmental perturbation, where immature properties are suppressed as a result of D2HG oncometabolite exposure. We propose that this defiance is likely a consequence of IDH1mt-associated epigenetic dysregulation and we identified biased DNA hydroxymethylation (5hmC) in maturation genes as a possible mechanism. Together, this study illustrates a novel cellular state aberration in GBM astrocyte lineage cells and presents new developmental targets for experimental and therapeutic exploration.
2024-10-31 | GSE276176 | GEO
Project description:Glioblastoma (GBM) is defined by heterogenous and resilient cell populations that closely reflect neurodevelopmental cell types. While it is clear that GBM echoes early and immature cell states, identifying the specific developmental programs disrupted in these tumors has been hindered by a lack of high-resolution trajectories of glial and neuronal lineages. Here, we delineate the course of human astrocyte maturation to uncover discrete developmental stages and attributes mirrored by GBM. We generated a transcriptomic and epigenomic map of human astrocyte maturation using cortical organoids maintained in culture for nearly two years. Through this approach, we chronicled a multi-phase developmental process orchestrated by a series of transcription factor and gene regulatory networks. Our time course of human astrocyte maturation includes a novel and molecularly distinct intermediate period that serves as a lineage commitment checkpoint upstream of mature quiescence. This intermediate stage acts as a site of developmental deviation separating IDH-wildtype neoplastic astrocyte lineage cells from quiescent astrocyte populations. Interestingly, IDH1-mutant tumor astrocyte lineage cells are the exception to this developmental perturbation, where immature properties are suppressed as a result of D2HG oncometabolite exposure. We propose that this defiance is likely a consequence of IDH1mt-associated epigenetic dysregulation and we identified biased DNA hydroxymethylation (5hmC) in maturation genes as a possible mechanism. Together, this study illustrates a novel cellular state aberration in GBM astrocyte lineage cells and presents new developmental targets for experimental and therapeutic exploration.
2024-10-31 | GSE276103 | GEO
Project description:Glioblastoma (GBM) is defined by heterogenous and resilient cell populations that closely reflect neurodevelopmental cell types. While it is clear that GBM echoes early and immature cell states, identifying the specific developmental programs disrupted in these tumors has been hindered by a lack of high-resolution trajectories of glial and neuronal lineages. Here, we delineate the course of human astrocyte maturation to uncover discrete developmental stages and attributes mirrored by GBM. We generated a transcriptomic and epigenomic map of human astrocyte maturation using cortical organoids maintained in culture for nearly two years. Through this approach, we chronicled a multi-phase developmental process orchestrated by a series of transcription factor and gene regulatory networks. Our time course of human astrocyte maturation includes a novel and molecularly distinct intermediate period that serves as a lineage commitment checkpoint upstream of mature quiescence. This intermediate stage acts as a site of developmental deviation separating IDH-wildtype neoplastic astrocyte lineage cells from quiescent astrocyte populations. Interestingly, IDH1-mutant tumor astrocyte lineage cells are the exception to this developmental perturbation, where immature properties are suppressed as a result of D2HG oncometabolite exposure. We propose that this defiance is likely a consequence of IDH1mt-associated epigenetic dysregulation and we identified biased DNA hydroxymethylation (5hmC) in maturation genes as a possible mechanism. Together, this study illustrates a novel cellular state aberration in GBM astrocyte lineage cells and presents new developmental targets for experimental and therapeutic exploration.
2024-10-31 | GSE276102 | GEO
Project description:Glioblastoma (GBM) is defined by heterogenous and resilient cell populations that closely reflect neurodevelopmental cell types. While it is clear that GBM echoes early and immature cell states, identifying the specific developmental programs disrupted in these tumors has been hindered by a lack of high-resolution trajectories of glial and neuronal lineages. Here, we delineate the course of human astrocyte maturation to uncover discrete developmental stages and attributes mirrored by GBM. We generated a transcriptomic and epigenomic map of human astrocyte maturation using cortical organoids maintained in culture for nearly two years. Through this approach, we chronicled a multi-phase developmental process orchestrated by a series of transcription factor and gene regulatory networks. Our time course of human astrocyte maturation includes a novel and molecularly distinct intermediate period that serves as a lineage commitment checkpoint upstream of mature quiescence. This intermediate stage acts as a site of developmental deviation separating IDH-wildtype neoplastic astrocyte lineage cells from quiescent astrocyte populations. Interestingly, IDH1-mutant tumor astrocyte lineage cells are the exception to this developmental perturbation, where immature properties are suppressed as a result of D2HG oncometabolite exposure. We propose that this defiance is likely a consequence of IDH1mt-associated epigenetic dysregulation and we identified biased DNA hydroxymethylation (5hmC) in maturation genes as a possible mechanism. Together, this study illustrates a novel cellular state aberration in GBM astrocyte lineage cells and presents new developmental targets for experimental and therapeutic exploration.
2024-10-31 | GSE276101 | GEO
Project description:A central question in glioblastoma multiforme (GBM) research is the identity of the tumor-initiating cell, and its contribution to the malignant phenotype and genomic state. We examine the potential of adult lineage-restricted progenitors to induce fully penetrant GBM using CNS progenitor-specific inducible Cre mice to mutate Nf1, Trp53, and Pten. We identify two phenotypically and molecularly distinct GBM subtypes governed by identical driver mutations. We demonstrate that the two subtypes arise from functionally independent pools of adult CNS progenitors. Despite histologic identity as GBM, these tumor types are separable based on the lineage of the tumor-initiating cell. These studies point to the cell of origin as a major determinant of GBM subtype diversity.
| S-EPMC4607935 | biostudies-literature
Project description:Glioblastomas (GBM) harbor subpopulations of therapy-resistant tumor initiating cells (TICs) that are self-renewing and multipotent. To understand the regulation of the TIC state, we performed an image-based screen for genes regulating GBM TIC maintenance and identified ZFHX4, a 397-kDa transcription factor. ZFHX4 is required to maintain TIC-associated phenotypes in vitro, suggesting that ZFHX4 regulates TIC differentiation, and its suppression increases glioma-free survival in intracranial xenografts. ZFHX4 interacts with CHD4, a core member of the NuRD (nucleosome remodeling and deacetylase) complex. ZFHX4 and CHD4 bind to overlapping sets of genomic loci and control similar gene expression programs. Using expression data derived from GBM patients, we demonstrate ZFHX4 is a master regulator of CHD4-mediated gene expression. These observations define ZFHX4 as a regulatory factor that links the chromatin remodeling NuRD complex and the GBM TIC state. Examination of binding of ZFHX4 and CHD4 across the human genome, using the 0308 tumor initiating cell line. Two replicates for each protein, compared to whole cell extract inputs.
2014-01-16 | E-GEOD-52419 | biostudies-arrayexpress
Project description:The purpose of this study is to determine whether the combination of two agents, INC280 and bevacizumab, is safe and effective when administered to patients with Glioblastoma Multiforme (GBM) who have progressed after receiving prior therapy or who have unresectable GBM.
| 2185625 | ecrin-mdr-crc