Regulatory Changes in Glioblastoma Brain Tumors and Xenografts
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PROVIDER: PRJNA478618 | ENA |
REPOSITORIES: ENA
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Project description:Regulatory Changes in Glioblastoma Brain Tumors and Xenografts
| PRJNA478619 | ENA
Project description:Regulatory Changes in Glioblastoma Brain Tumors and Xenografts
| PRJNA478618 | ENA
Project description:<p>Non-coding elements in our genomes that play critical roles in complex disease are frequently marked by highly unstable RNA species. Sequencing nascent RNAs attached to an actively transcribing RNA polymerase complex can identify unstable RNAs, including those templated from gene-distal enhancers (eRNAs). However, nascent RNA sequencing techniques remain challenging to apply in some cell lines and especially to intact tissues, limiting broad applications in fields such as cancer genomics and personalized medicine. Here we report the development of chromatin run-on and sequencing (ChRO-seq), a novel run-on technology that maps the location of RNA polymerase using virtually any frozen tissue sample, including samples with degraded RNA that are intractable to conventional RNA-seq. We used ChRO-seq to develop the first maps of nascent transcription in 23 human glioblastoma (GBM) brain tumors and patient derived xenografts. Remarkably, >90,000 distal enhancers discovered using the signature of eRNA biogenesis within primary GBMs closely resemble those found in the normal human brain, and diverge substantially from GBM cell models. Despite extensive overall similarity, 12% of enhancers in each GBM distinguish normal and malignant brain tissue. These enhancers drive regulatory programs similar to the developing nervous system and are enriched for transcription factor binding sites that specify a stem-like cell fate. These results demonstrate that GBMs largely retain the enhancer landscape associated with their tissue of origin, but selectively adopt regulatory programs that are responsible for driving stem-like cell properties. We also identified enhancers and their associated transcription factors that regulate genes characteristic of each known GBM subtype, and discovered a core group of transcription factors that control the expression of genes associated with clinical outcomes. This study uncovers new insights into the molecular etiology of GBM and introduces ChRO-seq which can now be used to map regulatory programs contributing to a variety of complex diseases.</p>
| phs001646 | dbGaP
Project description:Glioblastoma Multiforme (GBM) is the most deadly brain tumor, and currently lacks effective treatment options. Brain tumor initiating cells (BTICs) and orthotopic xenografts are widely used in investigating GBM biology and new therapies for this aggressive disease. However, the genomic characteristics and molecular resemblance of these models to GBM tumors remain undetermined. We used massively parallel sequencing technology to decode the genomes and transcriptomes of BTICs and xenografts and their matched tumors in order to delineate the potential impacts of the distinct growth environments. Using data generated from whole‐genome sequencing of 201 samples and RNA sequencing of 118 samples, we showed that typical GBM genomic driver alterations found in the tumors were retained in BTICs and xenografts. In contrast, gene expression and methylation profiles indicated higher levels of divergence, likely due to the different growth environment for each sample type. These findings suggest that a comprehensive genomic understanding of in vitro and in vivo GBM model systems is crucial for interpreting data from drug‐screens, and can help control for biases introduced by cell culture conditions and the microenvironment in mouse models.
2019-03-22 | GSE128654 | GEO
Project description:Glioblastoma (GBM) patient-derived orthotopic xenografts (PDOXs) were derived from organotypic spheroids obtained from patient tumor samples. To detect whether gene expression profiles of GBM patient tumors are retained in PDOXs, we performed genome-wide transcript analysis by human-specific microarrays . In parallel, we analyzed GBM cell cultures and corresponding intracranial xenografts from stem-like (NCH421k, NCH644) and adherent GBM cell lines (U87, U251). PDOXs show a better transcriptomic resemblance with patient tumors than other preclinical models. The major difference is largely explained by the depletion of human-derived non-malignant cells.
2020-07-01 | GSE134470 | GEO
Project description:Transcriptional profiling of glioblastoma orthotopic xenografts Descriptive experiment, comparison of 39 glioblastoma tumors as orthotopic xenografts
2012-07-10 | E-GEOD-38814 | biostudies-arrayexpress
Project description:DNA copy number profiling of 32 glioblastoma orthotopic xenografts Descriptive experiment, comparison of 39 glioblastoma tumors as orthotopic xenografts flow sorted for anueploidy
2012-07-10 | E-GEOD-38815 | biostudies-arrayexpress
Project description:Primary patient pediatric brain tumors from patients treated at SJCRH were implanted and amplified only in the brain of immunocompromised mice without tissue culture steps and referred as patient-derived orthotopic xenografts (Smith et al, Acta Neuropathologica, 2020).
| EGAS00001005533 | EGA
Project description:Development of model systems that recapitulate the molecular heterogeneity observed amongst GBM tumors will expedite the testing of targeted molecular therapeutic strategies for GBM treatment. In this study, we profiled DNA copy number and mRNA expression in 21 independent GBM tumor lines maintained as subcutaneous xenografts (GBMX), and compared GBMX molecular signatures to those observed in GBM clinical specimens derived from The Cancer Genome Atlas (TCGA). The predominant copy number signature in both tumor groups was defined by chromosome-7-gain/chromosome-10-loss, a poor prognosis genetic signature. We also observed, at frequencies similar to that detected in TCGA GBMs genomic amplification and overexpression of known GBM oncogenes such as EGFR, MDM2, CDK6 and MYCN, and novel genes including NUP107, SLC35E3, MMP1, MMP13 and DDX1. The transcriptional signature of GBMX tumors, which was stable over multiple subcutaneous passages, was defined by overexpression of genes involved in M-phase, DNA Replication, and Chromosome organization (MRC) and was highly similar to the poor-prognosis mitosis-and-cell-cycle-module (MCM) in GBM. Assessment of gene expression in TCGA-derived GBMs revealed overexpression of MRC cancer genes AURKB, BIRC5, CCNB1, CCNB2, CDC2, CDK2, and FOXM1, which form a transcriptional network important for G2/M- progression and/or -checkpoint activation. In conclusion, our study supports propagation of GBM tumors as subcutaneous xenografts as a useful approach for sustaining key molecular characteristics of patient tumors, and highlights therapeutic opportunities conferred by this GBMX tumor panel for testing targeted therapeutic strategies for GBM treatment. Keywords: Disease state analysis RNA expression was assessed in 38 samples: 34 GBM xenograft tumors (29 independent tumors with hybridization replicates for 5 tumors) and 4 non-neoplastic control brain samples
2009-03-07 | E-GEOD-14805 | biostudies-arrayexpress