Comprehensive genomic profiling of matched glioblastoma tumours, cell-lines, and xenografts reveals genomic stability and adaptation to disparate growth environments
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PROVIDER: EGAS00001002709 | EGA |
REPOSITORIES: EGA
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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:Despite the progress in medicine, no significant advancement in the standard of care for glioblastoma (GBM) patients have been reached. GBM heterogeneity, poor blood–brain barrier penetration and resistance to therapy highlight the need for new targets and clinical treatments. A step toward clinical translation includes the eradication of GBM Tumor-Initiating Cells (TICs), responsible for GBM heterogeneity and relapse. By using patient-derived TICs and xenograft orthotopic models, we demonstrate that Lysine-specific histone demethylase 1A (LSD1) is a druggable target in GBM. Here, we analyze the effect of LSD1i treatment on histone H3K4 in primary human cells and mouse brains.
2022-04-14 | PXD025781 | Pride
Project description:In the current study we focused on identifying an effective therapeutic regimen for a cohort of human-derived GBM models driven by alterations in the EGFR pathway. Pharmacological testing based on the genomics characteristic of each patient-derived model demonstrated that no single drug is efficacious in inhibiting tumor cell viability in culture. Combining two targeting agents Erlotinib (Tarceva) and MLN0128 (investigational MTOR inhibitor) resulted in effective tumor cell killing across several GBM PDX- derived culture models. Mechanistically, inhibition of p-ERK, p-AKT and RSK pathways underlie the combinatorial drug effects in culture. Using an orthotopic primary-GBM model, we show that the two drugs combined resulted in significant improvement in survival, superior to either drug alone. Microarray RNA profiling of tumor tissues from treated mice showed that the anti-tumor efficacy of co-inhibiting EGFR and MTOR pathways was in part due to modulation of the tumor microenvironment, including downregulation of CCL2 and Periostin, and subsequent inhibition of TAM infiltration in treated tumors.
2022-12-30 | GSE178147 | GEO
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. Disease state analysis
2009-03-07 | GSE14804 | GEO
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
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) heterogeneity in the genomic and phenotypic properties has potentiated personalized approach against specific therapeutic targets of each GBM patient. The Cancer Genome Atlas (TCGA) Research Network has been established the comprehensive genomic abnormalities of GBM, which sub-classified GBMs into 4 different molecular subtypes. The molecular subtypes could be utilized to develop personalized treatment strategy for each subtype. We applied a classifying method, NTP (Nearest Template Prediction) method to determine molecular subtype of each GBM patient and corresponding orthotopic xenograft animal model. The models were derived from GBM cells dissociated from patient's surgical sample. Specific drug candidates for each subtype were selected using an integrated pharmacological network database (PharmDB), which link drugs with subtype specific genes. Treatment effects of the drug candidates were determined by in vitro limiting dilution assay using patient-derived GBM cells primarily cultured from orthotopic xenograft tumors. The consistent identification of molecular subtype by the NTP method was validated using TCGA database. When subtypes were determined by the NTP method, orthotopic xenograft animal models faithfully maintained the molecular subtypes of parental tumors. Subtype specific drugs not only showed significant inhibition effects on the in vitro clonogenicity of patient-derived GBM cells but also synergistically reversed temozolomide resistance of MGMT-unmethylated patient-derived GBM cells. However, inhibitory effects on the clonogenicity were not totally subtype-specific. Personalized treatment approach based on genetic characteristics of each GBM could make better treatment outcomes of GBMs, although more sophisticated classifying techniques and subtype specific drugs need to be further elucidated. Gene expression profiling experiments were conducted for 25 patient-derived xenograft glioblastoma samples using Affymetrix Human Gene 1.0 ST arrays according to manufacturer's protocol.
2014-06-12 | E-GEOD-58400 | biostudies-arrayexpress
Project description:Glioblastoma (GBM) heterogeneity in the genomic and phenotypic properties has potentiated personalized approach against specific therapeutic targets of each GBM patient. The Cancer Genome Atlas (TCGA) Research Network has been established the comprehensive genomic abnormalities of GBM, which sub-classified GBMs into 4 different molecular subtypes. The molecular subtypes could be utilized to develop personalized treatment strategy for each subtype. We applied a classifying method, NTP (Nearest Template Prediction) method to determine molecular subtype of each GBM patient and corresponding orthotopic xenograft animal model. The models were derived from GBM cells dissociated from patient's surgical sample. Specific drug candidates for each subtype were selected using an integrated pharmacological network database (PharmDB), which link drugs with subtype specific genes. Treatment effects of the drug candidates were determined by in vitro limiting dilution assay using patient-derived GBM cells primarily cultured from orthotopic xenograft tumors. The consistent identification of molecular subtype by the NTP method was validated using TCGA database. When subtypes were determined by the NTP method, orthotopic xenograft animal models faithfully maintained the molecular subtypes of parental tumors. Subtype specific drugs not only showed significant inhibition effects on the in vitro clonogenicity of patient-derived GBM cells but also synergistically reversed temozolomide resistance of MGMT-unmethylated patient-derived GBM cells. However, inhibitory effects on the clonogenicity were not totally subtype-specific. Personalized treatment approach based on genetic characteristics of each GBM could make better treatment outcomes of GBMs, although more sophisticated classifying techniques and subtype specific drugs need to be further elucidated. Gene expression profiling experiments were conducted for 25 patient-derived xenograft glioblastoma samples using Affymetrix Human Gene 1.0 ST arrays according to manufacturer's protocol.
2014-06-12 | E-GEOD-58399 | biostudies-arrayexpress
Project description:Gene expression profile at single cell level of 17 orthotopic-patient derived xenografts from neuroblastoma samples. All xenografts were obtained through the St. Jude Childhood Solid Tumor Network (https://cstn.stjude.cloud/)
2024-05-15 | GSE228957 | GEO