Single-cell RNA-sequencing reveals that glioblastoma recapitulates a normal neurodevetlopmental hierarchy
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ABSTRACT:
PROVIDER: EGAS00001004422 | EGA |
REPOSITORIES: EGA
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2016-01-23 | GSE76234 | GEO
Project description:The neural stem cell marker CD133 is reported to identify cells within glioblastoma (GBM) that can initiate neurosphere growth and tumor formation, however, instances of CD133- cells exhibiting similar properties have also been reported. Here, we show that some PTEN-deficient GBM tumors produce a series of CD133+ and CD133- self-renewing tumor-initiating cell types and provide evidence that these cell types constitute a lineage hierarchy. Our results show that the capacities for self-renewal and tumor initiation in GBM need not be restricted to a uniform population of stem-like cells, but can be shared by a lineage of self-renewing cell types expressing a range of markers of forebrain lineage. Keywords: Expression and copy number analysis of glioblastomas and neurosphere forming derivative cell lines of same.
2010-04-22 | GSE19612 | GEO
Project description:RNA-binding proteins govern neural progenitor hierarchy during development and tumorigenesis
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Project description:Human glioblastomas (GBMs) are thought to harbour a subpopulation of glioblastoma stem cells (GSCs) that initiate tumour formation and regrowth following treatment. However, the origin of their proliferative heterogeneity during tumour growth pre- and post-treatment remains poorly understood. Here we study the clonal evolution of DNA barcoded GBMs following their serial propagation in xenograft mouse models to define the fate behaviour of individual GBM cells. Through quantitative analysis of clone sizes scored across multiple passages, we show that the growth of GBM clones in vivo are consistent with a remarkably neutral process resulting from a conserved proliferative hierarchy. In this model, slow-cycling stem-like cells give rise to a more rapidly cycling progenitor population with extensive self-maintenance capacity, that in turn generates short-lived cells that lack proliferative ability. We also identify rare "outlier" clones that deviate from these dynamics, and further show that chemotherapy reproducibly facilitates the selective expansion of pre-existing drug-resistant GBM lineages. Finally, we show that coexisting, functionally distinct GSCs may be targeted separately with epigenetic compounds. These findings show that, independent of an evolving mutational signature, the clonal dynamics of human GBM can be surprisingly robust, with intratumoural heterogeneity derived primarily from the defined stochastic fate behaviour of tumour cells within a conserved proliferative hierarchy.
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Project description:Glioblastoma stem cells (GSCs), are at the apex of its cellular hierarchy and contribute to glioblastoma progression and tumor recurrence. Gene expression profiling is useful in determining the genome-wide gene expression changes based on the experimental purpose. In order to interrogate the downstream targets of PTPRZ1, we applied gene expression profiling approach to screen the altered genes that are responsible for the functional phenotype changes. The results will provide a cue for mechanical analysis with potential translational values. PTPRZ1-knocking down glioblastoma stem cells (GSCs) and control GSCs were used in this study. RNA were isolated using Primescript RT Master Mix (Takara). Profiling was established by applying PrimeView Affymetrix Human Gene Expression Array.
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Project description:The neural stem cell marker CD133 is reported to identify cells within glioblastoma (GBM) that can initiate neurosphere growth and tumor formation, however, instances of CD133- cells exhibiting similar properties have also been reported. Here, we show that some PTEN-deficient GBM tumors produce a series of CD133+ and CD133- self-renewing tumor-initiating cell types and provide evidence that these cell types constitute a lineage hierarchy. Our results show that the capacities for self-renewal and tumor initiation in GBM need not be restricted to a uniform population of stem-like cells, but can be shared by a lineage of self-renewing cell types expressing a range of markers of forebrain lineage. Keywords: Expression and copy number analysis of glioblastomas and neurosphere forming derivative cell lines of same. DNA analysis and Expression profiling: DNA from patient tumor mincates was profiled for copy number changes on Affymetrix 500k chips and sequenced for mutations in exons 4-8 of p53 and exons 5&6 of PTEN. For determination of amplification, samples with mean relative copy number estimates of >3 for SNPs residing within the locus were scored as amplified. Copy number losses were determined using data from 30 SNPs within or immediately flanking the locus of interest. Relative copy number losses that were statistically significant at the p<.001 level were scored as losses regardless of the magnitude of the alteration. DNA from neurosphere lines was analyzed for copy number alterations by profiling on Agilent 244K arrays. Relative copy number estimates were determined using the GLAD segmentation algorithm. For expression profiling, RNA was extracted as previously described (Phillips et al., 2006) and profiled on Agilent WHG (for patient samples) or WHG 4x44 chips (for neurosphere lines and grafts) according to the manufacturer's (Agilent technologies, Palo Alto CA) protocol.
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Project description:Developmental fate decisions are dictated by master transcription factors (TFs) that interact with cis-regulatory elements to direct transcriptional programs. Certain malignant tumors may also depend on a cellular hierarchy reminiscent of normal development but superimposed on underlying genetic aberrations. In glioblastoma (GBM), a subset of stem-like tumor- propagating cells (TPCs) appears to drive tumor progression and underlie therapeutic resistance, yet remain poorly understood. Here, we identify a core set of neurodevelopmental TFs (POU3F2, SOX2, SALL2, OLIG2) essential for GBM propagation. These TFs coordinately bind and activate TPC-specific regulatory elements, and are sufficient to fully reprogram differentiated GBM cells to ‘induced’ TPCs that recapitulate the epigenetic landscape and phenotype of native TPCs. We reconstruct a TF network model that highlights critical interactions and identifies novel therapeutic targets for eliminating TPCs. Our study establishes the epigenetic basis of a developmental hierarchy in a devastating malignancy, provides detailed insight into the underlying gene regulatory programs, and suggests attendant therapeutic strategies. Histone modification profiling for H3K27ac and transcription factors in glioblastoma cell line reprogramming
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Project description:Self-pollen rejection in the Brassicaceae is determined by the diploid genotype of the pollen-producing plant, and it has long been known that the alleles show a dominance hierarchy. How this hierarchy is controlled and evolves has been a classical puzzle since the pre-molecular days of genetics. Here, we uncover the system of at least 17 small RNA (sRNA) producing loci and their multiple target sites that collectively control the dominance hierarchy among alleles of a self-incompatible Arabidopsis species. Our results demonstrate that natural selection shapes a dynamic repertoire of sRNA/targets interactions by jointly acting on sRNA genes, their processing precision and their target sites. It is remarkable that a single gene can evolve such a complex system of regulation among its own alleles. Sequencing of small RNAs from A. halleri floral buds, with this single exception (Al14, from A. lyrata).
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Project description:Brain tumour stem cells (BTSCs) are a population of self-renewing malignant stem cells that play an important role in glioblastoma tumour hierarchy and contribute to tumour growth, therapeutic resistance, and tumour relapse. Thus, targeting of BTSCs within the bulk of tumours represents a crucial therapeutic strategy. Here, we report that Edaravone is a potent drug that impairs BTSCs and impedes glioblastoma tumorigenesis. We show that Edaravone inhibits the self-renewal and growth of BTSCs harbouring a diverse range of oncogenic mutations without affecting non-oncogenic neural stem cells. Global gene expression profiling revealed that Edaravone significantly alters BTSC transcriptome and attenuates the expression of a large panel of genes involved in cell cycle progression, stemness, and DNA repair mechanisms. Mechanistically, we discovered that Edaravone directly targets Notchless homolog 1 (NLE1) and impairs Notch signalling pathway, alters the expression of stem cell markers, and sensitizes BTSC response to ionizing radiation (IR)-induced cell death. Importantly, we show that Edaravone treatment in preclinical models delays glioblastoma tumourigenesis, sensitizes their response to IR and prolongs the lifespan of animals. Our data suggest that repurposing of Edaravone is a promising therapeutic strategy for glioblastoma patients.
2024-11-19 | GSE261132 | GEO