Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA309314 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Smoothened (SMO)-inhibitors recently entered clinical trials for sonic-hedgehog driven medulloblastoma (SHH-MB). Clinical response appears highly variable. To understand the mechanism(s) of primary resistance and to identify pathways co-operating with aberrant SHH-signaling, we sequenced a large cohort of SHH-MBs across all age groups by sequencing, DNA methylation and expression profiling. Our data show that most adults but only half of the pediatric patients with SHH-MB will respond to SMO inhibition as predicted by molecular analysis of the primary tumor and tested in the SHH-xenografts, demonstrating that the next generation of SMO-inhibitor trials should be based on these predictive biomarkers. To further dissect the biological differences between the different age groups within SHH medulloblastomas, we looked at the transcriptomic profiles of SHH medulloblastoma samples. 73 medulloblastoma samples from patients of various ages were selected for RNA extraction and hybridization on Affymetrix Human Genome U133 Plus 2.0 Arrays.
2014-06-02 | E-GEOD-49243 | biostudies-arrayexpress
Project description:Smoothened (SMO)-inhibitors recently entered clinical trials for sonic-hedgehog driven medulloblastoma (SHH-MB). Clinical response appears highly variable. To understand the mechanism(s) of primary resistance and to identify pathways co-operating with aberrant SHH-signaling, we sequenced a large cohort of SHH-MBs across all age groups by sequencing, DNA methylation and expression profiling. Our data show that most adults but only half of the pediatric patients with SHH-MB will respond to SMO inhibition as predicted by molecular analysis of the primary tumor and tested in the SHH-xenografts, demonstrating that the next generation of SMO-inhibitor trials should be based on these predictive biomarkers. To further dissect the biological differences between the different age groups within SHH medulloblastomas, we looked at the DNA methylation profiles of SHH medulloblastoma samples. We investigated the DNA methylation profiles of 46 SHH medulloblastomas across all age groups using the Illumina 450k methylation array.
2014-09-02 | E-GEOD-49377 | biostudies-arrayexpress
Project description:Smoothened (SMO)-inhibitors recently entered clinical trials for sonic-hedgehog driven medulloblastoma (SHH-MB). Clinical response appears highly variable. To understand the mechanism(s) of primary resistance and to identify pathways co-operating with aberrant SHH-signaling, we sequenced a large cohort of SHH-MBs across all age groups by sequencing, DNA methylation and expression profiling. Our data show that most adults but only half of the pediatric patients with SHH-MB will respond to SMO inhibition as predicted by molecular analysis of the primary tumor and tested in the SHH-xenografts, demonstrating that the next generation of SMO-inhibitor trials should be based on these predictive biomarkers. To further dissect the biological differences between the different age groups within SHH medulloblastomas, we looked at the DNA methylation profiles of SHH medulloblastoma samples. We investigated the DNA methylation profiles of 83 SHH medulloblastomas across all age groups using the Illumina 450k methylation array.
2014-09-02 | E-GEOD-49576 | biostudies-arrayexpress
Project description:Smoothened (SMO)-inhibitors recently entered clinical trials for sonic-hedgehog driven medulloblastoma (SHH-MB). Clinical response appears highly variable. To understand the mechanism(s) of primary resistance and to identify pathways co-operating with aberrant SHH-signaling, we sequenced a large cohort of SHH-MBs across all age groups by sequencing, DNA methylation and expression profiling. Our data show that most adults but only half of the pediatric patients with SHH-MB will respond to SMO inhibition as predicted by molecular analysis of the primary tumor and tested in the SHH-xenografts, demonstrating that the next generation of SMO-inhibitor trials should be based on these predictive biomarkers. To further dissect the biological differences between the different age groups within SHH medulloblastomas, we looked at the transcriptomic profiles of SHH medulloblastoma samples.
2014-06-02 | GSE49243 | GEO
Project description:Smoothened (SMO)-inhibitors recently entered clinical trials for sonic-hedgehog driven medulloblastoma (SHH-MB). Clinical response appears highly variable. To understand the mechanism(s) of primary resistance and to identify pathways co-operating with aberrant SHH-signaling, we sequenced a large cohort of SHH-MBs across all age groups by sequencing, DNA methylation and expression profiling. Our data show that most adults but only half of the pediatric patients with SHH-MB will respond to SMO inhibition as predicted by molecular analysis of the primary tumor and tested in the SHH-xenografts, demonstrating that the next generation of SMO-inhibitor trials should be based on these predictive biomarkers. To further dissect the biological differences between the different age groups within SHH medulloblastomas, we looked at the DNA methylation profiles of SHH medulloblastoma samples.
2014-09-02 | GSE49576 | GEO
Project description:Smoothened (SMO)-inhibitors recently entered clinical trials for sonic-hedgehog driven medulloblastoma (SHH-MB). Clinical response appears highly variable. To understand the mechanism(s) of primary resistance and to identify pathways co-operating with aberrant SHH-signaling, we sequenced a large cohort of SHH-MBs across all age groups by sequencing, DNA methylation and expression profiling. Our data show that most adults but only half of the pediatric patients with SHH-MB will respond to SMO inhibition as predicted by molecular analysis of the primary tumor and tested in the SHH-xenografts, demonstrating that the next generation of SMO-inhibitor trials should be based on these predictive biomarkers. To further dissect the biological differences between the different age groups within SHH medulloblastomas, we looked at the DNA methylation profiles of SHH medulloblastoma samples.
2014-09-02 | GSE49377 | GEO
Project description:We used spatially resolved transcriptomics to define the cellular diversity within a sonic hedgehog (SHH) patient-derived model of Medulloblastoma (MB) and identify how cells specific to a transcriptional state or spatial location are pivotal in responses to treatment with the CDK4/6 inhibitor, Palbociclib. Our analysis reveals that SHH tumour in the mouse brain contains multiple malignant transcriptional states, recapitulating the extent of intratumoural cellular diversity identified in primary human SHH MB. Our study offers new insight into the previously described features of CDK4/6 inhibition in MB, with Palbociclib treatment inducing neuronal differentiation across all remaining cell types comprising the bulk of the SHH patient-derived orthotropic xenograft model. This study is, to the best of our knowledge, the first spatially resolved gene expression atlas of SHH PDOX MB and acts as proof-of-principle for the use of ST-seq in identifying spatially-organised tumour heterogeneity of MB.
2022-06-16 | E-MTAB-11720 | biostudies-arrayexpress
Project description:Medulloblastoma, the most common malignant pediatric brain tumor, is highly heterogeneous with distinct molecular subtypes and cellular origins. Although current treatments improve survival rates, patients suffer severe treatment-related side effects and often relapse of tumors carrying resistance mutations, underscoring an urgent need for alternative targeted therapies. Currently, the genetic alterations underlying this disease are not fully understood. Here we identify GNAS, encoding the G-protein Gs-alpha, as a potent tumor suppressor gene in medulloblastoma. GNAS specifically defines a subset of aggressive Sonic Hedgehog (Shh)-group medulloblastomas. Gnas loss-of-function in distinct lineage progenitors of the developing hindbrain suffices to initiate medulloblastoma. We find that Gs-alpha is highly enriched at primary cilia of granule neuron precursors and suppresses Shh signaling not only by regulating classic cAMP-dependent pathway but also controlling ciliary trafficking of Smoothened. Concurrent cAMP elevation and Smoothened inhibition robustly arrests tumor cell growth in Gnas mutants. We further reveal oligodendrocyte progenitors as a novel cellular origin for anatomically-distinct Shh-associated medulloblastomas. Together, we identify a previously unrecognized tumor suppressor function of Gs-alpha in medulloblastoma partially mediated through inhibiting Shh signaling, and uncover Gs-alpha as a molecular link across disparate cells of origin among Shh-group medulloblastomas, pointing to G- protein modulation as a potential therapeutic avenue. We isolated genomic DNAs from the cerebellum of adult wildtype mice and tumor tissue from individual GFAP-Gnas or Olig1-Gnas mutants and performed the Copy number variation analysis.
2014-08-24 | E-GEOD-60416 | biostudies-arrayexpress
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.
2022-06-02 | PXD034270 |
Project description:Medulloblastoma, the most common malignant pediatric brain tumor, is highly heterogeneous with distinct molecular subtypes and cellular origins. Although current treatments improve survival rates, patients suffer severe treatment-related side effects and often relapse of tumors carrying resistance mutations, underscoring an urgent need for alternative targeted therapies. Currently, the genetic alterations underlying this disease are not fully understood. Here we identify GNAS, encoding the G-protein Gs-alpha, as a potent tumor suppressor gene in medulloblastoma. GNAS specifically defines a subset of aggressive Sonic Hedgehog (Shh)-group medulloblastomas. Gnas loss-of-function in distinct lineage progenitors of the developing hindbrain suffices to initiate medulloblastoma. We find that Gs-alpha is highly enriched at primary cilia of granule neuron precursors and suppresses Shh signaling not only by regulating classic cAMP-dependent pathway but also controlling ciliary trafficking of Smoothened. Concurrent cAMP elevation and Smoothened inhibition robustly arrests tumor cell growth in Gnas mutants. We further reveal oligodendrocyte progenitors as a novel cellular origin for anatomically-distinct Shh-associated medulloblastomas. Together, we identify a previously unrecognized tumor suppressor function of Gs-alpha in medulloblastoma partially mediated through inhibiting Shh signaling, and uncover Gs-alpha as a molecular link across disparate cells of origin among Shh-group medulloblastomas, pointing to G- protein modulation as a potential therapeutic avenue. Transgenic medulloblastoma mouse models were analyzed by Affymetrix Mouse Gene 1.1 ST Array in order to determine their molecular subgroup. Tumors extracted from hGFAP:GnasCKO and Oligo1:GnasCKO transgenic mice were analyzed in 8 replicates each, together with normal mouse cerebellum.
2014-08-24 | E-GEOD-60417 | biostudies-arrayexpress