KMT2D suppresses Sonic Hedgehog-driven medulloblastoma progression and metastasis [ATAC-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA868710 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21013165_1.fastq.gz | Fastqsanger.gz | |||
| SRR21013165_2.fastq.gz | Fastqsanger.gz | |||
| SRR21013166_1.fastq.gz | Fastqsanger.gz | |||
| SRR21013166_2.fastq.gz | Fastqsanger.gz | |||
| SRR21013167_1.fastq.gz | Fastqsanger.gz |
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Project description:KMT2D suppresses Sonic Hedgehog-driven medulloblastoma progression and metastasis
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Project description:KMT2D suppresses Sonic Hedgehog-driven medulloblastoma progression and metastasis [RNA-seq]
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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
Project description:The major cause of treatment failure and mortality among medulloblastoma patients is metastasis intracranially or along the spinal cord. The molecular mechanisms driving tumor metastasis in Sonic hedgehog-driven medulloblastoma (SHH-MB) patients, however, remain largely unknown. In this study we define a tumor suppressive role of KMT2D (MLL2), a gene frequently mutated in the most metastatic β-subtype. Strikingly, genetic mouse models of SHH-MB demonstrate that heterozygous loss of Kmt2d in conjunction with activation of the SHH pathway causes highly penetrant disease with decreased survival, increased hindbrain invasion and spinal cord metastasis. Loss of Kmt2d attenuates neural differentiation and shifts the transcriptional/chromatin landscape of primary and metastatic tumors toward a decrease in differentiation genes and tumor suppressors and an increase in genes/pathways implicated in advanced stage cancer and metastasis (TGFβ, Notch, Atoh1, Sox2, and Myc). Thus, secondary heterozygous KMT2D mutations likely have prognostic value for identifying SHH-MB patients prone to develop metastasis.
| S-EPMC10562805 | biostudies-literature
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
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: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. Purpose: To known the gene expression profile of Medulloblastoma which drived by Gnas mutation Methods: mRNAs isolated from the cerebellum of control and Gnas mutants Results:Upregulation of Shh Signaling components in tumors Conclusions: The deletion of Gnas in hGFAP and Olig1 possitive cells result in substantial upregulation of shh signaling and formation of Medulloblastoma cerebellum mRNA profiles of 3 60-day old wild type (Ctrl) and 8 Olig1Cre driven Gsa conditional knockout or 8 hGFAPCre driven conditional knockout mice were generated by deep sequencing using Illumina Hiseq2000
2014-08-24 | E-GEOD-60415 | biostudies-arrayexpress
Project description:Sonic Hedgehog subgroup medulloblastomas
| PRJNA384622 | ENA
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.
2014-08-24 | GSE60416 | GEO