MYCN Drives Disparate Medulloblastoma from Human Embryonic and iPSC-Derived Stem Cells [array]
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ABSTRACT:
PROVIDER: PRJNA417801 | ENA |
REPOSITORIES: ENA
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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:MYCN Drives Disparate Medulloblastoma from Human Embryonic and iPSC-Derived Stem Cells
| PRJNA417799 | ENA
Project description:MYCN Drives Disparate Medulloblastoma from Human Embryonic and iPSC-Derived Stem Cells [seq]
| PRJNA417797 | 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 | GSE106725 | GEO
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: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:We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC gene family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this molecular group died of rapidly progressive disease post-relapse. To study this genetic interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of Trp53 function in this model produced aggressive tumors that mimicked the characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity, genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53–MYC interactions which emerge at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically. Using this dataset, assignation of medulloblastoma molecular subgroup by Illumina 450k microarray was performed for diagnostic and relapsed medulloblastoma samples to compare subgroup membership at diagnosis and relapse. We investigated the DNA methylation profiles of 18 diagnostic and 22 relapsing samples (including 15 diagnostic / relapse pairs) using the Illumina 450k methylation microarray
2015-04-23 | E-GEOD-62618 | biostudies-arrayexpress
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:PSEN1ΔE9, APPswe and APOE4 confer disparate phenotypes in human iPSC-derived microglia
| PRJNA559812 | ENA