Systems analysis of single-cell heterogeneity underlying glioma drug resistance
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PROVIDER: PRJNA1054676 | ENA |
REPOSITORIES: ENA
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Project description:Systems analysis of single-cell heterogeneity underlying glioma drug resistance
| PRJNA1054677 | ENA
Project description:Brain tumors are among the most malignant cancers and can arise from neural stem cells or oligodendrocyte progenitor cells (OPCs). Glioma-propagating cells (GPCs) that have stem-like properties have been derived from tumor variants such as glioblastoma multiforme (GBM) and oligodendroglial tumors, the latter being more chemosensitive with better prognosis. It has been suggested that such differences in chemosensitivity arise from the different profiles of OPCs versus neural stem cells. We thus explored if GPCs derived from these glioma variants can serve as reliable in vitro culture systems for studies. We utilized gene expression analyses, since GBM and oligodendrogliomas can be molecularly classified. Accordingly, we derived a gene signature distinguishing oligodendroglial GPCs from GBM GPCs collated from different studies, which was enriched for the Wnt, Notch and TGF-beta pathways. Using a novel method in glioma biology, the Connectivity Map, we mapped the strength of gene signature association with patient gene expression profiles in 2 independent glioma databases [GSE16011, http://caintegrator-info.nci.nih.gov/rembrandt]. Our gene signature consistently stratified survival in glioma patients. This data would suggest that in vitro low passage GPCs are similarly driven by transcriptomic changes that characterize the favorable outcome of oligodendrogliomas over GBM. Additionally, the gene signature was associated with the 1p/19q co-deletion status, the current clinical indicator of chemosensitivity. Our gene signature detects molecular heterogeneity in oligodendroglioma patients that cannot be accounted for by histology or the 1p/19q status alone, and highlights the limitation of morphology-based histological analyses in tumor classification, consequently impacting on treatment decisions. Total RNA obtained from primary neurosphere culture from brain tumor specimens of 6 patients were compared. Replicate arrays were performed for all 6 neurosphere cultures.
2012-06-02 | E-GEOD-31545 | biostudies-arrayexpress
Project description:Both established glioma cells lines U87MG and U373 were used for studying their interactions in the indirect co-cultures. Eventhough both being derived from the glioma tissue, those two cell lines prove morphologically and physiologically disctinct. Therefore their intre-cellular interactions were examined on gene exprexssion level in vitro to observe whether those co-cultures could make for a suitable in vitro cell model mimicking the in vivo glioma tumour heterogeneity. Three biological replicates of four cell set-ups were performed: U87MG monoculture, U373 monoculture, U87MG co-cultured with U373 (in Boyden chambers) and U373 co-cultured with U87MG (in Boyden chambers).
2015-04-08 | E-GEOD-59634 | biostudies-arrayexpress
Project description:High-grade gliomas are aggressive primary brain cancers with poor response to standard regimens, driven by immense heterogeneity. In isocitrate dehydrogenase (IDH) wild-type high-grade glioma (glioblastoma, GBM), increased intra-tumoral heterogeneity is associated with more aggressive disease. Recently, spatial technologies have emerged to dissect this complex heterogeneity within the tumor ecosystem by preserving cellular organization in situ. Here, we construct a high- resolution molecular landscape of GBM and IDH-mutant high-grade glioma patient samples to investigate the cellular subtypes and spatial communities that compose high-grade glioma using digital spatial profiling and spatial molecular imaging. This uncovered striking diversity of the tumor and immune microenvironment, that is embodied by the heterogeneity of the inferred copy- number alterations in the tumor. Reconstructing the tumor architecture revealed brain-intrinsic niches, composed of tumor cells reflecting brain cell types and microglia; and brain-extrinsic niches, populated by mesenchymal tumor cells and monocytes. We further reveal that cellular communication in these niches is underpinned by specific ligand-receptor pairs. This primary study reveals high levels of intra-tumoral heterogeneity in high-grade gliomas, associated with a diverse immune landscape within spatially localized regions.
2023-12-13 | GSE232469 | GEO
Project description:Drug resistance is a major cause for the failure of cancer chemotherapy or targeted therapy. However, the molecular regulatory mechanisms controlling the dynamic evolvement of drug resistance remain poorly understood. Thus, it is important to develop methods for unraveling gene regulatory mechanisms underlying the resistance to specific drugs. We used glioma differentiation therapy as a realistic case and time-course RNA-seq to investigate the temporal gene expression changes in sensitive and resistant cells. A computational method was developed to model and characterize the dynamic gene regulatory networks underlying cancer drug resistance based on time-course RNA-seq data.
2019-03-23 | GSE128722 | GEO
Project description:Both established glioma cells lines U87MG and U373 were used for studying their interactions in the indirect co-cultures. Eventhough both being derived from the glioma tissue, those two cell lines prove morphologically and physiologically disctinct. Therefore their intre-cellular interactions were examined on gene exprexssion level in vitro to observe whether those co-cultures could make for a suitable in vitro cell model mimicking the in vivo glioma tumour heterogeneity.
2015-04-08 | GSE59634 | GEO
Project description:Radiation is the frontline treatment for malignant gliomas. Intra-tumoral heterogeneity has been proposed to grant cancer cells a superior trajectory and survival advantage to avoid therapeutic interventions including radiation. However, direct evidence to support the hypothesis via the transcriptome dynamics of glioma during radiation therapy is limited. The current study aim to measure the functional subpopulation dynamics before and after radiation treatment that assist the radiation resistance at single cell resolution. We investigate the single cell transcriptome and biological pathways of primary glioma mouse model and post-radiation early/late time point. Specifically, we used the RCAS mouse model for gliomas, which overexpress PDGFRA as the model. Using single cell transcriptome, for the first time, we confirmed the proneural classification of PDGFRA RCAS glioma mouse model and its heterogeneity. We found that recurrent dominant subpopulations are featured with elevated proliferation rate and hypoxia. In addition, we identified a subpopulation of radiation resistant cells in at early time points with elevated stemness. Lastly, the subpopulations composition undergoes large changes at late time point when the tumor recurred. Single cell transcriptome profiling of radiation treated mouse glioma mouse model identified tumor cell subpopulations dynamics. It provides novel insights into the molecular phenotype and biological functions of radiation resistant tumor cell population.
2016-12-01 | GSE76184 | GEO
Project description:Brain tumors are among the most malignant cancers and can arise from neural stem cells or oligodendrocyte progenitor cells (OPCs). Glioma-propagating cells (GPCs) that have stem-like properties have been derived from tumor variants such as glioblastoma multiforme (GBM) and oligodendroglial tumors, the latter being more chemosensitive with better prognosis. It has been suggested that such differences in chemosensitivity arise from the different profiles of OPCs versus neural stem cells. We thus explored if GPCs derived from these glioma variants can serve as reliable in vitro culture systems for studies. We utilized gene expression analyses, since GBM and oligodendrogliomas can be molecularly classified. Accordingly, we derived a gene signature distinguishing oligodendroglial GPCs from GBM GPCs collated from different studies, which was enriched for the Wnt, Notch and TGF-beta pathways. Using a novel method in glioma biology, the Connectivity Map, we mapped the strength of gene signature association with patient gene expression profiles in 2 independent glioma databases [GSE16011, http://caintegrator-info.nci.nih.gov/rembrandt]. Our gene signature consistently stratified survival in glioma patients. This data would suggest that in vitro low passage GPCs are similarly driven by transcriptomic changes that characterize the favorable outcome of oligodendrogliomas over GBM. Additionally, the gene signature was associated with the 1p/19q co-deletion status, the current clinical indicator of chemosensitivity. Our gene signature detects molecular heterogeneity in oligodendroglioma patients that cannot be accounted for by histology or the 1p/19q status alone, and highlights the limitation of morphology-based histological analyses in tumor classification, consequently impacting on treatment decisions.
2012-06-03 | GSE31545 | GEO
Project description:To study the dynamics of GBM resistance and identify potential synergistic targets , we transfected PDGFR-amplified, patient-derived glioma neurospheres (TS543) with a barcoded lineage tracing library (CellTag), and treated the neurospheres with ispinesib. These genetically-modified, patient-derived neurospheres, which recapitulate key aspects of GBM heterogeneity, allow for surveillance of resistant phenotype on multiple timescales, and the barcode lineage tracing allows us to selectively analyze clones that are destined for resistance in the drug-naïve setting. We analyzed the phenotypes of the glioma cells during the long-term ispinesib treatment with single-cell RNAseq (scRNAseq), assess the stability and survival impact of drug-resistant phenotypes in the absence of drug and in orthotopic xenografts, and identified molecular markers of resistant clones in the drug-naïve setting to nominate effective drug combination.
2023-09-01 | GSE239651 | GEO
Project description:Although paediatric high grade gliomas resemble their adult counterparts in many ways, there appear to be distinct clinical and biological differences. One important factor hampering the development of new targeted therapies is the relative lack of cell lines derived from childhood glioma patients, as it is unclear whether the well-established adult lines commonly used are representative of the underlying molecular genetics of childhood tumours. We have carried out a detailed molecular and phenotypic characterisation of a series of paediatric high grade glioma cell lines in comparison to routinely used adult lines.
2009-09-21 | E-TABM-579 | biostudies-arrayexpress