Remodeling Group 3 medulloblastoma: MYC overexpression alone transforms progenitors of astrocytes and granule neurons in the postnatal cerebellum
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ABSTRACT:
PROVIDER: PRJNA472588 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7203690.fastq.gz | Fastqsanger.gz | |||
| SRR7203700.fastq.gz | Fastqsanger.gz | |||
| SRR7203691.fastq.gz | Fastqsanger.gz | |||
| SRR7203701.fastq.gz | Fastqsanger.gz | |||
| SRR7203692.fastq.gz | Fastqsanger.gz |
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Project description:Group 3 medulloblastoma is often associated with MYC amplification or overexpression, while whether MYC overexpression alone is sufficient to induce tumorigenesis is unknown and the cell type(s) which can be transformed by MYC is unclear. Here, by generating a new mouse model, we demonstrated that overexpression of Myc alone is sufficient to transform astrocyte progenitors and granule neuron progenitors (GNP) in the early postnatal cerebellum following orthotopic transplantation. The resulting tumors resemble human Group 3 medulloblastoma in terms of both histology and gene expression profiles. Using these models we found that inhibition of lactate dehydrogenase A (LDHA) significantly reduced both murine and human MYC-driven tumor growth, but did not affect SHH medulloblastoma, indicating that LDHA is potential and specific therapeutic target for MYC-driven medulloblastoma.
2019-04-25 | GSE114760 | GEO
Project description:Sonic hedgehog (Shh) signaling plays a critical role in regulating cerebellum development by maintaining the physiological proliferation of granule neuron precursors (GNPs), and its dysregulation leads to the oncogenesis of medulloblastoma. O-GlcNAcylation (O-GlcNAc) of proteins is an emerging regulator of brain function that maintains normal development and neuronal circuitry. Here, we demonstrate that O-GlcNAc transferase (OGT) in GNPs mediate the cerebellum development, and the progression of the Shh-subgroup of medulloblastoma. Specifically, OGT regulates the proliferation of GNPs by activating the Shh signaling pathway via O-GlcNAcylation at S355 of GLI family zinc finger 2 (Gli2), which in turn promotes its deacetylation and transcriptional activity via dissociation from p300, a histone acetyltransferases (HATs). Inhibition of OGT via genetic ablation or chemical inhibition improves survival in a medulloblastoma mouse model. These data uncover a critical role for O-GlcNAc signaling in cerebellar development, and pinpoint a potential therapeutic target for Shh-associated medulloblastoma.
| PXD034270 |
Project description:The progenitor/differentiation states of cerebellum granule cells have been investigated for many years. Deregulation of granule cells development is associated with the pathogenesis of medulloblastoma (MB).Our study reveals the cellular and spatial organization of cerebellar granule cells and provide direct evidence showing the similarity and discrepancy between normal development and tumorigenesis.
2021-01-18 | GSE156633 | GEO
Project description:Alternative pre-mRNA splicing critically contributes to the generation of protein variety in a tissue- and development-specific manner. Alterations in the normal pathways of alternative splicing (AS) have been associated with the growth and maintenance of several tumour types, and have been indicated as candidate bio-markers of tumour progression, metastasis and patient survival. In this study we applied genome-wide exon array technology to investigate AS events that may distinguish between human medulloblastoma and normal cerebellum. We initially investigated gene-level expression profiles to identify samples expressing gene signatures characteristic of previously described MB molecular subgroups. 3 medulloblastomas significantly over-expressed genes typically belonging to the Shh signalling pathway or associated with a granule cell progenitor status and were therefore classified as Shh-activated tumours (MB1). The remaining tumour samples were grouped together as medulloblastoma subset 2 (MB2). We then applied the Splicing Index algorithm and identified 1260 unique genes containing at least one candidate exon whose inclusion rate differed between different sample subgroups. Following the analysis of candidate event expression plots and gene structure annotation, we selected 14 examples of differential splicing of cassette exons and successfully validated 11 of them by semi-quantitative RT-PCR in a selection of the initial sample-set and subsequently in an independent set of 10 normal cerebellum and 20 medulloblastoma samples. Through the analysis of AS pathway in in vitro cultures of cerebellar granule cell progenitors (the putative cell of origin of least a subset of medulloblastomas), we showed that medulloblastoma-associated AS patterns could be indicative of a normal cerebellar undifferentiated phenotype and suggested that activation of oncogenic pathways during the development of the cerebellum may lead to a failure of neuronal differentiation also through the disruption of AS programs.
2011-01-01 | E-MTAB-292 | biostudies-arrayexpress
Project description:Origins of the brain tumor, medulloblastoma, from stem cells or restricted pro-genitor cells are unclear. To investigate this, we activated oncogenic Hedgehog signaling in multipotent and lineage-restricted CNS progenitors. We observed that normal unipo-tent cerebellar granule neuron precursors (CGNP) derive from hGFAP+ and Olig2+ rhombic lip progenitors. Hedgehog activation in a spectrum of early and late stage CNS progenitors generated similar medulloblastomas, but not other brain cancers, indicating that acquisition of CGNP identity is essential for tumorigenesis. We show in human and mouse medulloblastoma that cells expressing the glia-associated markers Gfap and Olig2 are neoplastic and that they retain features of embryonic-type granule lineage progenitors. Thus, oncogenic Hedgehog signaling promotes medulloblastoma from lineage-restricted granule cell progenitors. Gene expression profiling of cerebellar tumors generated from various early and late stage CNS progenitor cells. Experiment Overall Design: Group comparisons with biological replicates
2008-10-21 | E-GEOD-11859 | biostudies-arrayexpress
Project description:While medulloblastoma, a pediatric tumor of the cerebellum, is characterized by aberrations in developmental pathways, the majority of genetic determinants remain unknown. An unbiased Sleeping Beauty transposon screen revealed MyoD as a putative medulloblastoma tumor suppressor. This was unexpected, as MyoD is a muscle differentiation factor and not previously known to be expressed in cerebellum or medulloblastoma. In response to deletion of one allele of MyoD, two other Sonic hedgehog-driven mouse medulloblastoma models showed accelerated tumor formation and death, confirming MyoD as a tumor suppressor in these models. In normal cerebellum, MyoD was expressed in the proliferating granule neuron progenitors that are thought to be precursors to medulloblastoma. Similar to some other tumor suppressors that are induced in cancer, MyoD was expressed in proliferating medulloblastoma cells in three mouse models and in human medulloblastoma cases. This suggests that although expression of MyoD in a proliferating tumor is insufficient to prevent tumor progression, its expression in the cerebellum hinders medulloblastoma genesis. The goal of the gene expression analysis was to determine whether the canonical myogenic differentiation program was involved in increased tumorigenicity following loss of MyoD in the SHH-driven mouse models of medulloblastoma. We compared MyoD+/+; SmoA2 (n=3) with MyoD+/- ;SmoA2 mouse medulloblastoma tumors (n=2).
2013-09-27 | E-GEOD-51219 | biostudies-arrayexpress
Project description:While medulloblastoma, a pediatric tumor of the cerebellum, is characterized by aberrations in developmental pathways, the majority of genetic determinants remain unknown. An unbiased Sleeping Beauty transposon screen revealed MyoD as a putative medulloblastoma tumor suppressor. This was unexpected, as MyoD is a muscle differentiation factor and not previously known to be expressed in cerebellum or medulloblastoma. In response to deletion of one allele of MyoD, two other Sonic hedgehog-driven mouse medulloblastoma models showed accelerated tumor formation and death, confirming MyoD as a tumor suppressor in these models. In normal cerebellum, MyoD was expressed in the proliferating granule neuron progenitors that are thought to be precursors to medulloblastoma. Similar to some other tumor suppressors that are induced in cancer, MyoD was expressed in proliferating medulloblastoma cells in three mouse models and in human medulloblastoma cases. This suggests that although expression of MyoD in a proliferating tumor is insufficient to prevent tumor progression, its expression in the cerebellum hinders medulloblastoma genesis.
2013-09-27 | GSE51219 | GEO
Project description:Sonic hedgehog (Shh) signals via Gli transcription factors to stimulate proliferation of granule neuron precursor cells (GNPs) in the cerebellum. Deregulation of Shh target genes often results in unrestrained GNP proliferation and eventually medulloblastoma, the most common pediatric brain malignancy. Transcription factor binding location analysis (chIP-chip) revealed 510 and 1,060 genomic loci bound by Gli1 with high confidence in murine GNP and medulloblastoma cells, respectively. In primary tumors, Gli1 associated with only one-third of the Gli1-bound regions in GNPs. Gene expression profiling, coupled with our binding results, indicated that there were more than one hundred target genes in common between the two cell populations, and importantly, there was an equivalent number of tumor-specific targets. These results indicate that the transformation of normal GNPs into deadly tumor cells is accompanied by some changes in the battery of genes regulated by Gli1.
2010-06-03 | GSE17682 | GEO
Project description:Sonic hedgehog (Shh) signals via Gli transcription factors to stimulate proliferation of granule neuron precursor cells (GNPs) in the cerebellum. Deregulation of Shh target genes often results in unrestrained GNP proliferation and eventually medulloblastoma (MB), the most common pediatric brain malignancy. Gene expression profiling was coupled with transcription factor binding location analysis to determine the Gli1-controlled transcriptional regulatory networks in GNPs and medulloblastoma cells. We detected significant overlap, as well as differences, in the Gli1-controlled transcriptional regulatory networks in GNPs and MBs. We determined the presence of gene expression in each dataset. There were 9260 genes expressed in Gli1-FLAG GNPs and 9185 genes expressed in Gli1-FLAG;Ptc+/- tumors; 8691 of which are in common. The large overlap is consistent with the cellular origin of these tumors. When the genes detectably expressed were intersected with our binding data, there were only 132 putative Gli1 target genes shared by both cell populations. Due to the heightened activation of the Hh pathway in tumors relative to GNPs, we further deduced direct Gli1 target genes exclusive to tumors by determining significantly induced genes in tumors versus in Ptc+/- GNPs. We identified at least 116 tumor-specific Gli1 target genes. These data suggest that tumor formation is accompanied by a tremendous change in the battery of Gli target genes. Presence of gene expression was determined for all samples: Gli1-FLAG-expressing GNPs, Ptc+/- GNPs, and Gli1-FLAG;Ptc+/-medulloblastomas. These datasets were intersected with chIP-chip data to determine potential direct Gli1 target genes. Differential gene expression was determined by comparing expression profiles from medulloblastoma tumors to those from Ptc+/- GNPs.
2010-06-16 | E-GEOD-17702 | biostudies-arrayexpress
Project description:Medulloblastoma encompasses a collection of clinically and molecularly diverse tumor subtypes that together comprise the most common malignant childhood brain tumor. These tumors are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) following aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH-subtype). The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here, we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT-subtype), arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumors infiltrate the dorsal brainstem, while SHH-subtype tumors are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem that included aberrantly proliferating Zic1+ precursor cells. These lesions persisted in all mutant adult mice and in 15% of cases in which Tp53 was concurrently deleted, progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer. A total of 16 samples are analyzed, repsresenting 4 experimental groups: Ctnnb1 medulloblastoma (3 samples); Ptch1 medulloblastoma (6 samples); embryonic dorsal brainstem (4 samples); and postnatal granule neuron precursor cells (3 samples). Every sample was prepared from a different mouse.
2010-11-01 | E-GEOD-24628 | biostudies-arrayexpress