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Comparative epigenetic analysis of tumour initiating cells and syngeneic EPSC-derived neural stem cells in glioblastoma.

ABSTRACT: Epigenetic mechanisms which play an essential role in normal developmental processes, such as self-renewal and fate specification of neural stem cells (NSC) are also responsible for some of the changes in the glioblastoma (GBM) genome. Here we develop a strategy to compare the epigenetic and transcriptional make-up of primary GBM cells (GIC) with patient-matched expanded potential stem cell (EPSC)-derived NSC (iNSC). Using a comparative analysis of the transcriptome of syngeneic GIC/iNSC pairs, we identify a glycosaminoglycan (GAG)-mediated mechanism of recruitment of regulatory T cells (Tregs) in GBM. Integrated analysis of the transcriptome and DNA methylome of GBM cells identifies druggable target genes and patient-specific prediction of drug response in primary GIC cultures, which is validated in 3D and in vivo models. Taken together, we provide a proof of principle that this experimental pipeline has the potential to identify patient-specific disease mechanisms and druggable targets in GBM.

SUBMITTER: Vinel C

PROVIDER: S-EPMC8531305 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Glioblastoma-initiating cells: relationship with neural stem cells and the micro-environment.

Project description:Glioblastoma multiforme (GBM, WHO grade IV) is the most common and lethal subtype of primary brain tumor with a median overall survival of 15 months from the time of diagnosis. The presence in GBM of a cancer population displaying neural stem cell (NSC) properties as well as tumor-initiating abilities and resistance to current therapies suggests that these glioblastoma-initiating cells (GICs) play a central role in tumor development and are closely related to NSCs. However, it is nowadays still unclear whether GICs derive from NSCs, neural progenitor cells or differentiated cells such as astrocytes or oligodendrocytes. On the other hand, NSCs are located in specific regions of the adult brain called neurogenic niches that have been shown to control critical stem cell properties, to nourish NSCs and to support their self-renewal. This "seed-and-soil" relationship has also been adapted to cancer stem cell research as GICs also require a specific micro-environment to maintain their "stem cell" properties. In this review, we will discuss the controversies surrounding the origin and the identification of GBM stem cells and highlight the micro-environment impact on their biology.

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Project description:Glioblastoma multiforme (GBM) (grade IV astrocytoma) is the most common and aggressive primary brain tumor. GBM consists of heterogeneous cell types including a subset of stem cell-like cells thought to sustain tumor growth. These tumor-initiating glioblastoma multiforme-derived neural stem (GNS) cells as well as their genetically normal neural stem (NS) counterparts can be propagated in culture as relatively pure populations. Here, we perform quantitative proteomics to globally characterize and compare total proteome plus the secreted proteome (secretome) between GNS cells and NS cells. Proteins and pathways that distinguish malignant cancer (GNS) stem cells from their genetically normal counterparts (NS cells) might have value as new biomarkers or therapeutic targets. Our analysis identified and quantified ?7,500 proteins in the proteome and ?2,000 in the secretome, 447 and 138 of which were differentially expressed, respectively. Notable tumor-associated processes identified using gene set enrichment analysis included: extracellular matrix interactions, focal adhesion, cell motility, and cell signaling. We focused on differentially expressed surface proteins, and identified 26 that participate in ligand-receptor pairs that play a prominent role in tumorigenesis. Immunocytochemistry and immunoblotting confirmed that CD9, a recently identified marker of adult subventricular zone NS cells, was consistently enriched across a larger set of primary GNS cell lines. CD9 may, therefore, have value as a GNS-specific surface marker and a candidate therapeutic target. Altogether, these findings support the notion that increased cell-matrix and cell-cell adhesion molecules play a crucial role in promoting the tumor initiating and infiltrative properties of GNS cells. Stem Cells 2017;35:967-980.

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Comparative genomic hybridization by array of glioblastoma-derived neural stem cells

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2012-09-21 | E-MTAB-972 | biostudies-arrayexpress

Comparative genomic and genetic analysis of glioblastoma-derived brain tumor-initiating cells and their parent tumors.

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Comparative analysis of glioblastoma initiating cells and patient-matched EPSC-derived neural stem cells as a discovery tool and drug matching strategy

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

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Comparative analysis of glioblastoma initiating cells and patient-matched EPSC-derived neural stem cells as a discovery tool and drug matching strategy [array]

Project description:Malignant gliomas are the most common intrinsic brain tumors in adults and are associated with a very poor prognosis, which has not improved in the last 20 years. We show here that glioblastoma initiating cells (GIC) and syngeneic neural stem cells derived from enhanced pluripotent stem cells (iNSC) are a suitable novel pre-clinical pipeline to discover new patient-specific disease mechanisms and to identify druggable targets for personalized therapy.

2021-09-17 | GSE155985 | GEO

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