Transcriptomic analysis of metastatic Sonic Hedgehog subgroup medulloblastomas
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE98299 | GEO | 2017/04/28
SECONDARY ACCESSION(S): PRJNA384627
REPOSITORIES: GEO
Similar Datasets
Project description:We report findings that illuminate a dynamic metastasis pathway in the common pediatric brain tumor medulloblastoma.
2017-04-28 | GSE98298 | GEO
Project description:We report findings that illuminate a dynamic metastasis pathway in the common pediatric brain tumor medulloblastoma.
2017-04-28 | GSE98300 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-04-28 | GSE98302 | GEO
Project description:Sonic Hedgehog subgroup medulloblastomas
| PRJNA384622 | ENA
Project description:Medulloblastoma arising from the cerebellum is the most common pediatric brain malignancy, with leptomeningeal metastases often present at diagnosis and recurrence associated with poor clinical outcome. In this study, we used mouse medulloblastoma models to explore the relationship of tumor pathophysiology and dysregulated expression of the NOTCH pathway transcription factor ATOH1, which is present in aggressive medulloblastoma subtypes driven by aberrant Sonic Hedgehog/Patched (SHH/PTCH) signaling. In experiments with conditional ATOH1 mouse mutants crossed to Ptch1+/- mice, which develop SHH-driven medulloblastoma, animals with Atoh1 transgene expression developed highly penetrant medulloblastoma at a young age with extensive leptomeningeal disease and metastasis to the spinal cord and brain, resembling xenografts of human SHH medulloblastoma. Metastatic tumors retained abnormal SHH signaling like tumor xenografts. Conversely, ATOH1 expression was detected consistently in recurrent and metastatic SHH medulloblastoma. Chromatin immunoprecipitation sequencing and gene expression profiling identified candidate ATOH1 targets in tumor cells involved in development and tumorigenesis. Among these targets specific to metastatic tumors, there was an enrichment in those implicated in extracellular matrix remodeling activity, cytoskeletal network and interaction with microenvironment, indicating a shift in transcriptomic and epigenomic landscapes during metastasis. Treatment with bone morphogenetic protein or SHH pathway inhibitors decreased tumor cell proliferation and suppressed metastatic tumor growth, respectively. Our work reveals a dynamic ATOH1-driven molecular cascade underlying medulloblastoma metastasis that offers possible therapeutic opportunities. Cancer Res; 77(14); 3766-77. ©2017 AACR.
| S-EPMC5512702 | biostudies-literature
Project description:Medulloblastoma is the most common malignant pediatric brain tumor, and mechanisms underlying its development are poorly understood. We identified recurrent amplification of the miR-17/92 polycistron proto-oncogene in 6% of pediatric medulloblastomas by high-resolution single-nucleotide polymorphism genotyping arrays and subsequent interphase fluorescence in situ hybridization on a human medulloblastoma tissue microarray. Profiling the expression of 427 mature microRNAs (miRNA) in a series of 90 primary human medulloblastomas revealed that components of the miR-17/92 polycistron are the most highly up-regulated miRNAs in medulloblastoma. Expression of miR-17/92 was highest in the subgroup of medulloblastomas associated with activation of the sonic hedgehog (Shh) signaling pathway compared with other subgroups of medulloblastoma. Medulloblastomas in which miR-17/92 was up-regulated also had elevated levels of MYC/MYCN expression. Consistent with its regulation by Shh, we observed that Shh treatment of primary cerebellar granule neuron precursors (CGNP), proposed cells of origin for the Shh-associated medulloblastomas, resulted in increased miR-17/92 expression. In CGNPs, the Shh effector N-myc, but not Gli1, induced miR-17/92 expression. Ectopic miR-17/92 expression in CGNPs synergized with exogenous Shh to increase proliferation and also enabled them to proliferate in the absence of Shh. We conclude that miR-17/92 is a positive effector of Shh-mediated proliferation and that aberrant expression/amplification of this miR confers a growth advantage to medulloblastomas.
2010-04-02 | GSE21166 | GEO
Project description:Medulloblastoma is the most common malignant pediatric brain tumor, and mechanisms underlying its development are poorly understood. We identified recurrent amplification of the miR-17/92 polycistron proto-oncogene in 6% of pediatric medulloblastomas by high-resolution single-nucleotide polymorphism genotyping arrays and subsequent interphase fluorescence in situ hybridization on a human medulloblastoma tissue microarray. Profiling the expression of 427 mature microRNAs (miRNA) in a series of 90 primary human medulloblastomas revealed that components of the miR-17/92 polycistron are the most highly up-regulated miRNAs in medulloblastoma. Expression of miR-17/92 was highest in the subgroup of medulloblastomas associated with activation of the sonic hedgehog (Shh) signaling pathway compared with other subgroups of medulloblastoma. Medulloblastomas in which miR-17/92 was up-regulated also had elevated levels of MYC/MYCN expression. Consistent with its regulation by Shh, we observed that Shh treatment of primary cerebellar granule neuron precursors (CGNP), proposed cells of origin for the Shh-associated medulloblastomas, resulted in increased miR-17/92 expression. In CGNPs, the Shh effector N-myc, but not Gli1, induced miR-17/92 expression. Ectopic miR-17/92 expression in CGNPs synergized with exogenous Shh to increase proliferation and also enabled them to proliferate in the absence of Shh. We conclude that miR-17/92 is a positive effector of Shh-mediated proliferation and that aberrant expression/amplification of this miR confers a growth advantage to medulloblastomas. A total of 90 primary medulloblastoma specimens were profiled by Affymetrix exon array and gene-level analysis was performed.
2010-04-14 | E-GEOD-21166 | biostudies-arrayexpress
Project description:Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients. Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MBSHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MBSHH. Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHH subtype and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNAs modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MBSHH are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems. Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide strong rationale for further investigating the role of protein homeostasis in other pediatric and adult cancer types and potential opportunities for novel therapeutic interference.
2020-04-23 | PXD016832 | Pride
Project description:The major cause for treatment failure, morbidity and mortality amongst medulloblastoma patients is metastasis intracranially or along the spinal cord. The molecular mechanisms driving tumor metastasis in SHH-driven medulloblastoma (SHH-MB) patients remain largely unknown. In this study we used mouse models of SHH-MB to define a tumor suppressive role of KMT2D (MLL4), a gene frequently mutated in the most metastatic β-subtype. Strikingly, heterozygous loss of Kmt2d in conjunction with aberrant activation of the SHH pathway causes highly penetrant disease with decreased survival, hindbrain invasion and spinal cord metastasis. Loss of Kmt2d shifts the transcriptional and chromatin landscape of primary and metastatic tumor cells to preferentially upregulate pathways and genes associated with advanced stage cancer and metastasis including TGFβ, Notch, Atoh1, Sox2/9 and Myc. Our study provides strong evidence that secondary mutations in KMT2D will have prognostic value for identifying SHH-MB patients that are likely to develop metastasis.
2023-10-25 | GSE211029 | GEO
Project description:The major cause for treatment failure, morbidity and mortality amongst medulloblastoma patients is metastasis intracranially or along the spinal cord. The molecular mechanisms driving tumor metastasis in SHH-driven medulloblastoma (SHH-MB) patients remain largely unknown. In this study we used mouse models of SHH-MB to define a tumor suppressive role of KMT2D (MLL4), a gene frequently mutated in the most metastatic β-subtype. Strikingly, heterozygous loss of Kmt2d in conjunction with aberrant activation of the SHH pathway causes highly penetrant disease with decreased survival, hindbrain invasion and spinal cord metastasis. Loss of Kmt2d shifts the transcriptional and chromatin landscape of primary and metastatic tumor cells to preferentially upregulate pathways and genes associated with advanced stage cancer and metastasis including TGFβ, Notch, Atoh1, Sox2/9 and Myc. Our study provides strong evidence that secondary mutations in KMT2D will have prognostic value for identifying SHH-MB patients that are likely to develop metastasis.
2023-10-25 | GSE210990 | GEO