Transcriptomic analysis of MYC-inhibited Medulloblastoma-derived D283 Med cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA718454 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14102277_1.fastq.gz | Fastqsanger.gz | |||
| SRR14102277_2.fastq.gz | Fastqsanger.gz | |||
| SRR14102278_1.fastq.gz | Fastqsanger.gz | |||
| SRR14102278_2.fastq.gz | Fastqsanger.gz | |||
| SRR14102279_1.fastq.gz | Fastqsanger.gz |
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Project description:Medulloblastoma is one of the most common malignant pediatric brain tumors. Group 3 is the most aggressive molecular subgroup, showing the highest rate of metastasis at diagnosis. To date, very few long noncoding RNAs have been implicated in Group 3 Medulloblastoma biology. Here, we identified the long noncoding RNAs dependent on the activity of the MYC oncogene, the major driver gene of Group 3 Medulloblastoma.
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2017-11-16 | GSE106959 | GEO
Project description:We describe an 8 year old child who had disseminated anaplastic medulloblastoma and a deleterious heterozygous BRCA2 6174delT germline mutation. Molecular profiling was consistent with Group 4 medulloblastoma. The posterior fossa mass was resected and the patient received intensive chemotherapy and craniospinal irradiation. Despite this, the patient succumbed to a second recurrence of his medulloblastoma, which presented eight months after diagnosis as malignant pleural and peritoneal effusions. Continuous medulloblastoma cell lines were isolated from the original tumor (CHLA-01-MED) and the malignant pleural effusion (CHLA-01R-MED). Here we provide their analyses, including in vitro and in vivo growth, drug sensitivity, comparative genomic hybridization and next generation sequencing analysis. In addition to the BRCA2 6174delT, the medulloblastoma cells had amplification of MYC, deletion at Xp11.2 and isochromosome 17, but no structural variations or overexpression of GFI1 or GFI1B. To our knowledge, this is the first pair of diagnosis/recurrence medulloblastoma cell lines, the only medulloblastoma cell lines with BRCA2 6174delT described to date, and the first reported case of a child with medulloblastoma associated with a germline BRCA2 6174delT who did not also have Fanconi anemia. Continuous medulloblastoma cell lines were isolated from the original tumor (CHLA-01-MED) and the malignant pleural effusion (CHLA-01R-MED). Here we provide their analyses, including in vitro and in vivo growth, drug sensitivity, comparative genomic hybridization with Agilent 400k CGH arrays and whole transcriptome RNASeq analysis.
2015-07-06 | E-GEOD-70003 | biostudies-arrayexpress
Project description:Deregulation of N-myc is a leading cause of malignant brain tumors in children. To target N-myc-driven medulloblastoma, most research has focused on identifying genomic alterations or on the analysis of the medulloblastoma transcriptome. Here, we have broadly characterized the translatome of medulloblastoma and shown that N-myc unexpectedly drives selective translation of transcripts that promote protein homeostasis. Cancer cells are constantly exposed to proteotoxic stress associated with alterations in protein production or folding. It remains poorly understood how cancers cope with proteotoxic stress to promote their growth. Here, our data unexpectedly revealed that N-myc regulates the expression of specific components (~5%) of the protein folding machinery at the translational level through the major cap binding protein, eukaryotic initiation factor eIF4E. Reducing eIF4E levels in mouse models of medulloblastoma blocked tumorigenesis. Importantly, targeting Hsp70, a protein folding chaperone translationally regulated by N-myc, suppressed tumor growth in mouse and human medulloblastoma xenograft models. These findings reveal a previously hidden molecular program that promotes medulloblastoma formation and identify new therapies that may have impact in the clinic.
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Project description:In this experiment, we identify MYC binding sites in the medulloblastoma cell line ONS76. The purpose of this experiment was to identify genes bound by MYC and compare MYC bound genes to genes differentially expressed when SOX2 or omomyc were elevated in ONS76 cells.
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Project description:RNA sequencing of medulloblastoma cell lines DAOY and USP13-med; wild type and VAPB KO.
2023-06-28 | E-MTAB-11914 | biostudies-arrayexpress
Project description:Medulloblastoma (MB) is the most common malignant brain tumor in children. Patients whose tumors exhibit overexpression or amplification of the MYC oncogene (c-MYC) usually have an extremely poor prognosis, but there are no animal models of this subtype of the disease. Here we show that cerebellar stem cells expressing Myc and mutant Trp53 (p53) generate aggressive tumors following orthotopic transplantation. These tumors consist of large, pleiomorphic cells and resemble human MYC-driven MB at a molecular level. Notably, antagonists of PI3K/mTOR signaling, but not Hedgehog signaling, inhibit growth of tumor cells. These findings suggest that cerebellar stem cells can give rise to MYC-driven MB, and identify a novel model that can be used to test therapies for this devastating disease. To gain insight into the pathways that control growth of MYC-driven MB, we compared gene expression profiles of murine Myc/DNp53 (MP) tumor cells to those of freshly isolated cerebellar stem cells (Prom1+Lin- cells) and of tumors from Ptch1 mutant mice (a model for Sonic Hedgehog-associated MB). RNA was isolated from stem cells and tumor cells using the RNAqueous kit (Ambion). RNA was labeled and hybridized to Affymetrix Mouse Genome 430 2.0 arrays. 19 mouse cell samples (stem cells and tumor cells) were analyzed. There are four groups of samples, three with five biological replicates and the last with four (one outlier was removed). To gain insight into the mechanisms of transformation into tumors, we compared the gene expression profiles of MP tumor cells derived from stem cells (Myc/DNp53-infected Prom1+Lin- cells, designated MP-pl) or progenitors (Myc/DNp53-infected Prom1+ cells, designated MP-p) to gene expression profiles of uninfected stem cells (designated NSC) and profiles from a distinct model of medulloblastoma, the patched mutant mouse (designated ptch1).
2011-12-05 | E-GEOD-34126 | biostudies-arrayexpress
Project description:We describe an 8 year old child who had disseminated anaplastic medulloblastoma and a deleterious heterozygous BRCA2 6174delT germline mutation. Molecular profiling was consistent with Group 4 medulloblastoma. The posterior fossa mass was resected and the patient received intensive chemotherapy and craniospinal irradiation. Despite this, the patient succumbed to a second recurrence of his medulloblastoma, which presented eight months after diagnosis as malignant pleural and peritoneal effusions. Continuous medulloblastoma cell lines were isolated from the original tumor (CHLA-01-MED) and the malignant pleural effusion (CHLA-01R-MED). Here we provide their analyses, including in vitro and in vivo growth, drug sensitivity, comparative genomic hybridization and next generation sequencing analysis. In addition to the BRCA2 6174delT, the medulloblastoma cells had amplification of MYC, deletion at Xp11.2 and isochromosome 17, but no structural variations or overexpression of GFI1 or GFI1B. To our knowledge, this is the first pair of diagnosis/recurrence medulloblastoma cell lines, the only medulloblastoma cell lines with BRCA2 6174delT described to date, and the first reported case of a child with medulloblastoma associated with a germline BRCA2 6174delT who did not also have Fanconi anemia.
2015-07-06 | GSE70003 | GEO
Project description:Time-course hypoxia incubation (1% O2) of D283-Med medulloblastoma cells
| PRJNA418498 | ENA
Project description:Aberrant oncogenic activation of MYC drives tumorigenesis in the most aggressive subset of medulloblastoma, the most common malignant brain tumor in childhood. Metastatic dissemination at diagnosis and at recurrence is commonly observed in MYC-driven medulloblastomas. Since these tumors display remarkable resistance to standard multimodal therapeutic approaches, epigenetic modulators commonly altered in these tumors are highly promising targets for novel therapeutic approaches. Here, we report on a cross-entity, high-throughput epigenetic drug screen to evaluate therapeutic vulnerabilities in the most common malignant primary brain tumors. Specifically, we performed a primary screen including 78 epigenetic inhibitors and a secondary screen including 20 histone deacetylase inhibitors (HDACi) to compare response profiles in atypical teratoid/rhabdoid tumor (AT/RT, n=11), medulloblastoma (n=14), and glioblastoma (n=14). This unbiased approach revealed preferential activity of HDACi in MYC-driven medulloblastoma. Importantly, the class I selective HDACi CI-994 showed significant cell viability reduction mediated by induction of apoptosis in MYC-driven medulloblastoma, with little to no activity in non-MYC-driven medulloblastoma, AT/RT, and glioblastoma in vitro. Notably, CI-994 displayed antitumoral effects at the primary site and the metastatic compartment in two orthotopic mouse models of MYC-driven medulloblastoma. Furthermore, synergistic drug screening and RNA sequencing revealed NFκB pathway induction as a mechanism of resistance to CI-994 treatment. Taken together, our findings identified MYC pathway activation as a predictive biomarker for epigenetic treatment intervention in high-risk medulloblastoma and provide a preclinical rationale for further exploration of CI-994 combined with NFκB pathway inhibitors in the treatment of MYC-driven medulloblastoma.
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