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KMT2D suppresses Sonic Hedgehog-driven medulloblastoma progression and metastasis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE211030 | GEO | 2023/10/25

REPOSITORIES: GEO

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KMT2D suppresses Sonic hedgehog-driven medulloblastoma progression and metastasis.

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

KMT2D suppresses Sonic Hedgehog-driven medulloblastoma progression and metastasis [ATAC-seq]

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

KMT2D suppresses Sonic Hedgehog-driven medulloblastoma progression and metastasis [RNA-seq]

2023-10-25 | GSE210990 | GEO

KMT2D suppresses Sonic Hedgehog-driven medulloblastoma progression and metastasis

Project description:KMT2D suppresses Sonic Hedgehog-driven medulloblastoma progression and metastasis

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KMT2D suppresses Sonic Hedgehog-driven medulloblastoma progression and metastasis [ATAC-seq]

Project description:KMT2D suppresses Sonic Hedgehog-driven medulloblastoma progression and metastasis [ATAC-seq]

| PRJNA868710 | ENA

KMT2D suppresses Sonic Hedgehog-driven medulloblastoma progression and metastasis [RNA-seq]

Project description:KMT2D suppresses Sonic Hedgehog-driven medulloblastoma progression and metastasis [RNA-seq]

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The G-protein Alpha Subunit Gs? Is A Tumor Suppressor In Sonic Hedgehog-driven Medulloblastoma

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-08-24 | E-GEOD-53248 | biostudies-arrayexpress

Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma.

Project description:Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease.

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The G-protein Alpha Subunit Gsα Is A Tumor Suppressor In Sonic Hedgehog-driven Medulloblastoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2014-08-24 | GSE53248 | GEO

Loss of Pin1 Suppresses Hedgehog-Driven Medulloblastoma Tumorigenesis.

Project description:Medulloblastoma is the most common malignant brain tumor in children. Therapeutic approaches to medulloblastoma (combination of surgery, radiotherapy, and chemotherapy) have led to significant improvements, but these are achieved at a high cost to quality of life. Alternative therapeutic approaches are needed. Genetic mutations leading to the activation of the Hedgehog pathway drive tumorigenesis in ~30% of medulloblastoma. In a yeast two-hybrid proteomic screen, we discovered a novel interaction between GLI1, a key transcription factor for the mediation of Hedgehog signals, and PIN1, a peptidylprolyl cis/trans isomerase that regulates the postphosphorylation fate of its targets. The GLI1/PIN1 interaction was validated by reciprocal pulldowns using epitope-tagged proteins in HEK293T cells as well as by co-immunoprecipiations of the endogenous proteins in a medulloblastoma cell line. Our results support a molecular model in which PIN1 promotes GLI1 protein abundance, thus contributing to the positive regulation of Hedgehog signals. Most importantly, in vivo functional analyses of Pin1 in the GFAP-tTA;TRE-SmoA1 mouse model of Hedgehog-driven medulloblastoma demonstrate that the loss of Pin1 impairs tumor development and dramatically increases survival. In summary, the discovery of the GLI1/PIN1 interaction uncovers PIN1 as a novel therapeutic target in Hedgehog-driven medulloblastoma tumorigenesis.

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