MYCN Drives Disparate Medulloblastoma from Human Embryonic and iPSC-Derived Stem Cells
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PROVIDER: PRJNA417799 | ENA |
REPOSITORIES: ENA
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Project description:MYCN Drives Disparate Medulloblastoma from Human Embryonic and iPSC-Derived Stem Cells [seq]
| PRJNA417797 | ENA
Project description:MYCN Drives Disparate Medulloblastoma from Human Embryonic and iPSC-Derived Stem Cells [array]
| PRJNA417801 | ENA
Project description:How tumors develop or respond to therapies vary significantly among species. Here we report that medulloblastoma (MB) the most frequent malignant childhood brain tumor can develop from human hindbrain neuro-epithelial stem (hbNES) cells or induced pluripotent stem cell (iPSC)-derived NES (NES) cells via MYCN overexpression in mice. NES tumors developed fast with leptomeningeal dissemination, while hbNES tumors formed significantly later with no dissemination. By using large cohorts of MB patients we show that tumors resemble a common subgroup of Sonic Hedgehog (SHH) MBs and that pluripotency and mTOR signaling correlate with poor prognosis. To conclude, both iPSC-derived and embryonic NES cells can be transformed into distinct humanized MB models valuable for identifying better diagnostic markers and drug targets.
2020-01-27 | GSE106727 | GEO
Project description:How tumors develop or respond to therapies vary significantly among species. Here we report that medulloblastoma (MB) the most frequent malignant childhood brain tumor can develop from human hindbrain neuro-epithelial stem (hbNES) cells or induced pluripotent stem cell (iPSC)-derived NES (NES) cells via MYCN overexpression in mice. NES tumors developed fast with leptomeningeal dissemination, while hbNES tumors formed significantly later with no dissemination. By using large cohorts of MB patients we show that tumors resemble a common subgroup of Sonic Hedgehog (SHH) MBs and that pluripotency and mTOR signaling correlate with poor prognosis. To conclude, both iPSC-derived and embryonic NES cells can be transformed into distinct humanized MB models valuable for identifying better diagnostic markers and drug targets.
2020-01-27 | GSE106725 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE34280: Clonal Selection Drives Genetic Divergence of Metastatic Medulloblastoma [Affymetrix SNP6 Arrays] GSE34355: Clonal Selection Drives Genetic Divergence of Metastatic Medulloblastoma [Illumina Infinium HumanMethylation27 Beadchip v1.2] Refer to individual Series
2011-12-13 | E-GEOD-34356 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-01-27 | GSE106728 | GEO
Project description:BACKGROUND Focal high-level amplifications of MYC define a subset of high-risk medulloblastoma patients. However, the prognostic role of MYCN oncogene amplification remains less clear. We aimed to evaluate the prognostic value of this alteration alone and in combination with biological modifiers in a large cohort of 67 pediatric medulloblastomas with MYCN amplification (MYCN-MB). METHODS Twenty-one MYCN-MB with MYCN amplication and 56 MYCN-MB were respectively examined using either gene expression profiling and array-CGH, or immunohistochemical analysis and FISH. All 67 tumors were further subject to mutational analyses. Semi non-negative matrix factorization–based and unsupervised hierarchical clustering methods were used to identify biological groups. We compared molecular, clinical, and prognostic characteristics both within biological MYCN-MB groups and with non-amplified tumors. RESULTS Transcriptomic analysis of this large cohort of MYCN-MBs demonstrated a significant enrichment of MYCN-MB in the SHH and group D variants. Further substantiating this biological dichotomy of MYCN-MB, respective group affiliations were also accompanied by variant-specific cytogenetic aberrations including deletion of 9q in the SHH variant, and gain of 7q and isochromosome 17q/17q gain in MYCN-MBs clustering with group D tumors. Among clinically relevant variables, SHH subtype and 10q loss for Non-SHH tumors comprised the most powerful markers of favorable prognosis in MYCN-MB. CONCLUSION We demonstrate considerable heterogeneity within MYCN-MB in terms of genetics, tumor biology, and clinical outcome. Thus, assessment of disease group and 10q copy-number status may improve risk stratification of this group and may delineate MYCN-MB with the same dismal prognosis as MYC amplified tumors. Furthermore, based on the enrichment of MYCN and GLI2 amplifications in SHH-driven medulloblastoma, amplification of these downstream signaling intermediates should be excluded before a patient is enrolled into a clinical trial using a Smoothened inhibitor.
2011-09-01 | GSE30530 | GEO
Project description:PRC2 Heterogeneity Drives Tumor Growth in Medulloblastoma
| PRJNA848783 | ENA
Project description:MYCN amplification in neuroblastoma leads to aberrant expression of MYCN oncoprotein, which binds active genes promoting transcriptional amplification. Yet how MYCN coordinates transcription elongation to meet productive transcriptional amplification and which elongation machinery represents MYCN-driven vulnerability remain to be identified. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastomas. MYCN directly binds EAF1 and recruits SEC to enhance processive transcription elongation. Depletion of EAF1 or AFF1/AFF4, another core subunit of SEC, leads to a global reduction in transcription elongation and elicits selective apoptosis of MYCN-amplified neuroblastoma cells. A combination screen reveals SEC inhibition synergistically potentiates the therapeutic efficacies of FDA-approved BCL2 antagonist ABT-199, in part due to suppression of MCL1 expression, both in MYCN-amplified neuroblastoma cells and in patient-derived xenografts. These findings identify disruption of the MYCN-SEC regulatory axis as a promising therapeutic strategy in neuroblastoma.
2023-05-10 | PXD039332 | Pride
Project description:The transcription factor OTX2 has been implicated as an oncogene in medulloblastoma, which is the most common malignant brain tumor in children. It is highly expressed in most medulloblastomas and amplified in a subset of them. The role of OTX2 in medulloblastoma and its downstream targets are unclear. Therefore, we generated D425 medulloblastoma cells in which we can silence endogenous OTX2 by inducible shRNA. Silencing of OTX2 strongly inhibited cell proliferation and resulted in a neuronal-like differentiation. Expression profiling of time courses after silencing showed a progressive change in gene expression for many cellular processes. Down regulated genes were highly enriched for cell cycle and visual perception genes, while up regulated genes were enriched for genes involved in development and differentiation. This shift in expression profiles is reminiscent to changes described to occur during normal cerebellum development. OTX2 is expressed in proliferating granular progenitor cells, but the expression diminishes when these cells exit the cell cycle and start differentiating. ChIP-on-chip analyses of OTX2 in D425 cells showed that cell cycle and perception genes were direct OTX2 targets, while regulation of most differentiation genes appears to be indirect. These analyses provide the first insight in the molecular network of OTX2, demonstrating that OTX2 is essential in medulloblastoma and directly drives proliferation by regulating the expression of cell cycle genes. Since many of these genes also correlate in expression with OTX2 in primary tumors, they might be potential targets for therapy in medulloblastoma patients. Keywords: OTX2, medulloblastoma, mRNA profiling *** This Series represents the gene expression component of the study. Three independent time course experiments of OTX2 silencing, and 1 control experiment in D425 medulloblastoma cells.
2012-07-03 | E-GEOD-22875 | biostudies-arrayexpress