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

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

PROVIDER: PRJNA902278 | ENA |

REPOSITORIES: ENA

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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.

2023-07-01 | GSE218076 | GEO

Olig2 targetome in SHH subgroup of medulloblastoma

Project description:Several basic helix-loop-helix (bHLH) transcription factors are upregulated in Sonic Hedgehog subgroup of medulloblastoma (SHH MB). Olig2, a neural bHLH transcription factor known to regulate differentiation of neural cell populations, is broadly expressed in mouse models of SHH MB. ChIP-Seq of Olig2 revealed its binding to a large number of sites near genes known to promote SHH MB tumorigenesis, suggesting a potential role for Olig2 in regulating transcriptional programme of MB.

2024-03-23 | GSE103824 | GEO

Identification of genes involved in SHH subgroup medulloblastoma using murine whole-body Sleeping Beauty insertional mutagenesis

2013-07-09 | GSE43994 | GEO

Identification of genes involved in SHH subgroup medulloblastoma using murine whole-body Sleeping Beauty insertional mutagenesis

Project description:Ptch+/- mice, which are predisposed to SHH subgroup medulloblastoma, were mutagenised using the Sleeping Beauty transposon to identify genes which increase the frequency of medulloblastoma formation. Gene expression in tumours was assessed both to investigate their relationship to human subgroup tumours, and to identify genes where expression was altered by mutagenesis. Total RNA isolated from tumours induced by SB mutagenesis were compared to normal cerebellum, tumours induced witout SB mutagenesis, and tumours from a distinct model of disease (GTML).

2013-07-09 | E-GEOD-43994 | biostudies-arrayexpress

Inhibition of WNT signaling attenuates self-renewal of SHH-subgroup medulloblastoma.

Project description:The SMOOTHENED inhibitor vismodegib is FDA approved for advanced basal cell carcinoma (BCC), and shows promise in clinical trials for SONIC HEDGEHOG (SHH)-subgroup medulloblastoma (MB) patients. Clinical experience with BCC patients shows that continuous exposure to vismodegib is necessary to prevent tumor recurrence, suggesting the existence of a vismodegib-resistant reservoir of tumor-propagating cells. We isolated such tumor-propagating cells from a mouse model of SHH-subgroup MB and grew them as sphere cultures. These cultures were enriched for the MB progenitor marker SOX2 and formed tumors in vivo. Moreover, while their ability to self-renew was resistant to SHH inhibitors, as has been previously suggested, this self-renewal was instead WNT-dependent. We show here that loss of Trp53 activates canonical WNT signaling in these SOX2-enriched cultures. Importantly, a small molecule WNT inhibitor was able to reduce the propagation and growth of SHH-subgroup MB in vivo, in an on-target manner, leading to increased survival. Our results imply that the tumor-propagating cells driving the growth of bulk SHH-dependent MB are themselves WNT dependent. Further, our data suggest combination therapy with WNT and SHH inhibitors as a therapeutic strategy in patients with SHH-subgroup MB, in order to decrease the tumor recurrence commonly observed in patients treated with vismodegib.

| S-EPMC5680121 | biostudies-literature

Macrophages in SHH subgroup medulloblastoma display dynamic heterogeneity that varies with treatment modality

Project description:Macrophages in SHH subgroup medulloblastoma display dynamic heterogeneity that varies with treatment modality

| PRJNA701617 | ENA

Sufu and Spop cooperate to suppress SHH medulloblastoma tumorigenesis via regulation of Gli2 protein stability [ChIP-seq]

Project description:GLI2 overexpression is a hallmark in SHH subgroup of medulloblastoma (SHH MB). Here we identify the targetome of Gli2 in two mouse models of SHH MB: SmoM2 overexpression and Sufu;Spop double knockout MB.

2018-12-13 | GSE112702 | GEO

Sufu and Spop cooperate to suppress SHH medulloblastoma tumorigenesis via regulation of Gli2 protein stability [RNA-seq]

Project description:GLI2 overexpression is a hallmark in SHH subgroup of medulloblastoma (SHH MB). Here we profile the transcriptome of two mouse models of SHH MB expressing high Gli2: SmoM2 overexpression and Sufu;Spop double knockout MB.

2018-12-13 | GSE112772 | GEO

Determining the chromatin accessibility profiles of functionally distinct SHH-medulloblastoma sub-populations

Project description:Using FACS sorting on SOX2-eGFP and MKi67-RFP mice on a Ptch1+/- background, we identified cycling& non-cycling stem cells and tumor bulk subpopulations in endpoint mouse SHH-subgroup medulloblastoma tumors, and determined their chromatin accessibility progiles to identify unique regulators of cell state.

2024-09-11 | GSE233993 | GEO

O-GlcNAcylation Promotes Cerebellum Development and Medulloblastoma Oncogenesis via SHH Signaling

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 |

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