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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE210990 | GEO | 2023/10/25

REPOSITORIES: GEO

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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

AMPK attenuates SHH subgroup medulloblastoma growth and metastasis by inhibiting NF-kB activation

Project description:Background: Medulloblastoma (MB) is one of the most common malignant pediatric brain tumors. Metastasis and relapse are the leading causes of death in MB patients. The initiation of the SHH subgroup of MB (SHH-MB) is due to the aberrant activation of Sonic Hedgehog (Shh) signaling. However, the mechanisms for its metastasis are still unknown. Results: AMP-dependent protein kinase (AMPK) restrains the activation of Shh signaling pathway, thereby impeding the proliferation of SHH-MB cells. More importantly, AMPK also hinders the growth and metastasis of SHH-MB cells by regulating NF-kB signaling pathway. Furthermore, Vismodegib and TPCA-1, which block the Shh and NF-kB pathways, respectively, synergistically restrained the growth, migration, and invasion of SHH-MB cells. Conclusions: This work demonstrates that AMPK functions through two signaling pathways, SHH-GLI1 and NF-kB. AMPK-NF-kB axis is a potential target for molecular therapy of SHH-MB, and the combinational blockade of NF-kB and Shh pathways confers synergy for SHH-MB therapy.

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Gene expression data from medulloblastoma tumor samples

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.

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Methylation profiling data from medulloblastoma tumor samples

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

Methylation data from medulloblastoma tumor samples

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

RAS/MAPK activation drives resistance to Smo inhibition, metastasis and tumor evolution in Shh pathway-dependent tumors

Project description:Aberrant Shh signaling promotes tumor growth in diverse human cancers. The importance of Shh signaling is particularly evident in medulloblastoma and basal cell carcinoma (BCC), where inhibitors targeting the Shh pathway component Smoothened (Smo) show great therapeutic promise. However, the emergence of drug resistance limits long-term efficacy and the mechanisms of resistance remain poorly understood. Using new culturing techniques, we established a cohort of Shh pathway-driven medulloblastoma cell lines derived from Ptch+/- mice. Using this new model, we identify activation of the RAS/MAPK pathway circumvents Shh pathway-dependency, drives tumor growth and enhances metastatic behavior.Together these findings reveal a critical role of RAS/MAPK pathway in drug resistance and tumor evolution of Shh pathway-dependent tumors. We performed gene expression profile analysis of SMB cells, in vivo primary MB, as well as cerebellum of normal P6 and adult mice. We also compared gene expression profiles of SMB cells to those of growth factor treated and RAS transformed cells. 24 mouse samples were collected for RNA extraction and hybridization on Affymetrix microarrays, including 3 normal cerebellar as control, 3 primary tumor samples and 18 cell samples with different treatment conditions. We first compared gene expression profiles of SMB cells to those of in vivo primary MB and normal cerebellum. We then compared gene expression profiles of SMB cells to those of growth factor treated and RAS transformed cells.

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MYC promotes aggressive growth and metastasis of a WNT-medulloblastoma mouse model

Project description:Medulloblastoma (MB), the most common malignant pediatric brain tumor, comprises of four molecularly and clinically distinct subgroups (termed WNT, SHH, Group3, and Group4). Prognosis varies based on genetic and pathological features associated with each molecular subgroup. WNT-MB, considered low-risk, are rarely metastatic and contain activating mutations in CTNNB1; Group3-MB, commonly classified as high-risk, are frequently metastatic and can contain genomic alterations resulting in elevated MYC expression. Here we compare model systems of low-risk WNT-MB to high-risk Group3-MB to identify tumor and microenvironment interactions that could contribute to features associated with poor outcome. Compared to Group3-MB, we find that WNT-MB display enrichment in gene sets related to extracellular matrix (ECM) regulation and cellular adhesion. Exogenous expression of MycT58A in murine WNT-MB models significantly accelerates growth and results in metastatic disease. In addition to down-regulation of ECM regulation and cell adhesion pathways, we also identified immune system interactions among the top down-regulated signaling pathways following MycT58A expression. Taken together, our data provides evidence that increased Myc signaling can promote the growth and metastasis of WNT-MB.

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Gene expression data from medulloblastoma tumor samples

2014-06-02 | GSE49243 | GEO

Methylation data from medulloblastoma tumor samples

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

Methylation profiling data from medulloblastoma tumor samples

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.

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