Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA338477 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Inhibition of Medulloblastoma growth by a sonic hedgehog (SHH) inhibitor
| PRJNA309314 | ENA
Project description:Sonic hedgehog signaling in maxillary development
| PRJDB14668 | ENA
Project description:Here, we studied the effects of oHSV C134 in two syngeneic medulloblastoma mouse models, one that aligns with the sonic hedgehog (SHH) subtype (MYCN) and another that aligns with tumors of the group 3 subtype (CMYC).We harvested tumor tissue two and six days post-injection of C134 and performed single cell RNA-sequencing (scRNA-seq).
2023-07-27 | GSE200008 | GEO
Project description:Aberrant sonic hedeghog signaling is implicated in the development of various cancer entities such as medulloblastoma. The canonical signaling cascade has been studied for years. Activation of GLI transcription factors was revealed as the driving force upon pathway activation. Phosphorylation by Proteinkinase A, Casein Kinase 1 and Glycogen Synthase Kinase 3 β has been found to influence the degradation of the GLI transcription factors. However, the deeper role of phosphorylation in the signal transduction remains unclear. We, therefore, applied comprehensive HPLC-MS/MS based phosphoproteomics to reveal phosphorylation dynamics underlying the chemical activation and inhibition of sonic hedgehog signaling in human medulloblastoma cells. Human medulloblastoma cells were treated with SAG (Hh pathway induction) and Vismodegib (Hh pathway inhibition) for 5 and 15 minutes. Our phosphoproteomic profiling revealed a central role of phosphorylation in the regulation of ciliary assembly, trafficking and signal transduction after 5 minutes treatment. ERK/MAPK signaling besides protein kinase A signaling and mTOR signaling were differentially regulated. Activation of Polo-like kinase 1 and inhibtion of Caseinkinase 2A1 was characteristic for Vismodegib treatment while SAG treatment induced Aurora kinase A activity. Distinctive phosphorylation of central players of sonic Hh signaling such as Smoothened, SUFU, Gli2 and Gli3 was obtained after 15 minutes treatment.
2021-09-08 | PXD013408 | Pride
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
Project description:The morphogen and mitogen, Sonic Hedgehog, activates a Gli1-dependent transcription program that drives proliferation of granule neuron progenitors (GNPs) within the external germinal layer of the postnatally developing cerebellum. Medulloblastomas with mutations activating the Sonic Hedgehog signaling pathway preferentially arise within the external germinal layer, and the tumor cells closely resemble GNPs. Atoh1/Math1, a basic helix-loop-helix transcription factor essential for GNP histogenesis, does not induce medulloblastomas when expressed in primary mouse GNPs that are explanted from the early postnatal cerebellum and transplanted back into the brains of naïve mice. However, enforced expression of Atoh1 in primary GNPs enhances the oncogenicity of cells overexpressing Gli1 by almost three orders of magnitude. Unlike Gli1, Atoh1 cannot support GNP proliferation in the absence of Sonic Hedgehog signaling and does not govern expression of canonical cell cycle genes. Instead, Atoh1 maintains GNPs in a Sonic Hedgehog-responsive state by regulating genes that trigger neuronal differentiation, including many expressed in response to bone morphogenic protein-4. Therefore, by targeting multiple genes regulating the differentiation state of GNPs, Atoh1 collaborates with the pro-proliferative Gli1-dependent transcriptional program to influence medulloblastoma development. Keywords: disease state analysis 14 samples, 1 time series, 2 engineered Medulloblastoma tumors
2010-07-08 | E-GEOD-19684 | biostudies-arrayexpress
Project description:Germline loss-of-function (LOF) variants in Elongator complex protein 1 (ELP1) are the most prevalent predisposing genetic events in childhood medulloblastoma (MB), accounting for ~30% of the Sonic Hedgehog (SHH) 3 subtype. The underlying mechanism(s) by which germline ELP1 deficiency provokes SHH-MB pathogenesis remain unknown. Genetically engineered mice mimicking heterozygous germline Elp1 LOF (Elp1HET) seen in affected germline carriers exhibit hallmark features of cancer predisposition in cerebellar granule neuron progenitors (GNPs), including increased DNA replication stress, genomic instability, accelerated cell cycle, and stalled differentiation. Orthotopic transplantation of Elp1HET GNPs harboring somatic Ptch1 inactivation yielded SHH-MB-like tumors with compromised p53 signaling, providing an explanation for the exclusivity of ELP1-associated MBs in SHH-3 subtype. Preclinical treatment of ELP1-mutant patient-derived xenografts with an FDA-approved HDM2 inhibitor reactivated p53-dependent apoptosis and extended survival. Our findings functionally substantiate the role of ELP1 deficiency in SHH-MB predisposition and nominate therapeutics that overcome p53 inhibition as a rational treatment option.
2025-04-11 | PXD050487 | Pride
Project description:Germline loss-of-function (LOF) variants in Elongator complex protein 1 (ELP1) are the most prevalent predisposing genetic events in childhood medulloblastoma (MB), accounting for ~30% of the Sonic Hedgehog (SHH) 3 subtype. The underlying mechanism(s) by which germline ELP1 deficiency provokes SHH-MB pathogenesis remain unknown. Genetically engineered mice mimicking heterozygous germline Elp1 LOF (Elp1HET) seen in affected germline carriers exhibit hallmark features of cancer predisposition in cerebellar granule neuron progenitors (GNPs), including increased DNA replication stress, genomic instability, accelerated cell cycle, and stalled differentiation. Orthotopic transplantation of Elp1HET GNPs harboring somatic Ptch1 inactivation yielded SHH-MB-like tumors with compromised p53 signaling, providing an explanation for the exclusivity of ELP1-associated MBs in SHH-3 subtype. Preclinical treatment of ELP1-mutant patient-derived xenografts with an FDA-approved HDM2 inhibitor reactivated p53-dependent apoptosis and extended survival. Our findings functionally substantiate the role of ELP1 deficiency in SHH-MB predisposition and nominate therapeutics that overcome p53 inhibition as a rational treatment option.
2025-04-11 | PXD050488 | Pride
Project description:Primary cilia shape postnatal astrocyte development through Sonic hedgehog signaling
| PRJNA1165324 | ENA
Project description:In bladder, loss of mammalian Sonic Hedgehog (Shh) accompanies progression to invasive urothelial carcinoma, but the molecular mechanisms underlying this cancer-initiating event are poorly defined. Here, we show that loss of Shh results from hypermethylation of the CpG shore of the Shh gene, and that inhibition of DNA methylation increases Shh expression to halt the initiation of murine urothelial carcinoma at the early stage of progression. In full-fledged tumors, pharmacologic augmentation of Hedgehog (Hh) pathway activity impedes tumor growth, and this cancer-restraining effect of Hh signaling is mediated by the stromal response to Shh signals, which stimulates subtype conversion of basal to luminal-like urothelial carcinoma. Our findings thus provide a basis to develop subtype-specific strategies for the management of human bladder cancer.
2019-04-09 | GSE129441 | GEO