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A forward genetic screen identifies potassium channel essentiality in SHH medulloblastoma maintenance [DNA-seq]

ABSTRACT: A forward genetic screen identifies potassium channel essentiality in SHH medulloblastoma maintenance [DNA-seq]

PROVIDER: PRJNA1160900 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30664048_1.fastq.gz	Fastqsanger.gz
	SRR30664048_2.fastq.gz	Fastqsanger.gz
	SRR30664049_1.fastq.gz	Fastqsanger.gz
	SRR30664049_2.fastq.gz	Fastqsanger.gz
	SRR30664050_1.fastq.gz	Fastqsanger.gz

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A forward genetic screen identifies potassium channel essentiality in SHH medulloblastoma maintenance [RNA-seq]

Project description:A forward genetic screen identifies potassium channel essentiality in SHH medulloblastoma maintenance [RNA-seq]

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A forward genetic screen identifies potassium channel essentiality in SHH medulloblastoma maintenance [DNA-seq]

Project description:Sequencing cancer genomes is predicted to uncover therapeutic tumor vulnerabilities. This has been complicated by the abundance of genetic alterations which are either non-functional, or only important in tumor initiation or progression. Distinguishing tumor maintenance genes from initiation, progression, and passenger genes is critical for developing effective cancer therapy. We employed a functional genomic approach using the Lazy Piggy transposon to identify tumor maintenance genes in vivo, and apply this to SHH medulloblastoma (MB). Combining Lazy Piggy screening in mice and transcriptomic profiling of human MB, we discovered candidate maintenance genes including the voltage-gated potassium channel Kcnb2. Genetic knockout of Kcnb2 impairs MB growth. Kcnb2 mediates potassium efflux in MB-propagating cells to govern cell volume. Loss of Kcnb2 leads to chronic osmotic swelling and decreased plasma membrane tension, which elevates endocytosis to dampen Egfr signaling, thereby mitigating proliferation of MB-propagating cells. Kcnb2 is largely dispensable for mouse development and synergizes with anti-SHH therapy in treating MB. These results demonstrate the utility of the Lazy Piggy functional genomic approach in identifying cancer maintenance genes, and elucidate a mechanism by which a potassium channel integrates biomechanical and biochemical signaling to promote MB aggression.

2024-09-16 | GSE277172 | GEO

A forward genetic screen identifies potassium channel essentiality in SHH medulloblastoma maintenance [RNA-seq]

2024-09-16 | GSE277171 | GEO

In vivo functional genomics identifies essentiality of potassium homeostasis in medulloblastoma

Project description:In vivo functional genomics identifies essentiality of potassium homeostasis in medulloblastoma

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SHH medulloblastoma samples

Project description:Sequencing data of human SHH medulloblastoma samples

| EGAS00001000607 | EGA

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

Developmental Basis of SHH Medulloblastoma Heterogeneity

Project description:Single-Nucleus RNA-Sequencing and Single-Cell RNA-Sequencing from SHH Medulloblastoma Tumors with MBEN histology

2023-11-21 | GSE214469 | GEO

Developmental Basis of SHH Medulloblastoma Heterogeneity

Project description:Developmental Basis of SHH Medulloblastoma Heterogeneity

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Acute Crebbp knockout in postnatally induced Shh medulloblastoma [tumor]

Project description:Recurrent mutations in chromatin modifiers are specifically prevalent in adolescent or adult patients with Sonic Hedgehog-associated medulloblastoma (SHH MB). Here, we report that mutations in the acetyltransferase CREBBP have opposing effects during the development of the cerebellum, the primary site of origin of SHH MB. Our data reveal that loss of Crebbp in cerebellar granule neuron progenitors (GNPs) during embryonic development of mice compromises GNP development, in part by downregulation of brain-derived neurotrophic factor (Bdnf). Interestingly, concomitant cerebellar hypoplasia was also observed in patients with Rubinstein-Taybi syndrome, a congenital disorder caused by germline mutations of CREBBP. By contrast, loss of Crebbp in GNPs during postnatal development synergizes with oncogenic activation of SHH signaling to drive MB growth, thereby explaining the enrichment of somatic CREBBP mutations in SHH MB of adult patients. Together, our data provide novel insights into time-sensitive consequences of CREBBP mutations and corresponding associations with human diseases. We used microarrays to detail the global programme of gene expression underlying the knockout of Crebbp in murine Shh medulloblastoma, acutely induced at postnatal stages of development.

2017-11-22 | GSE107253 | 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.

2023-07-01 | GSE218076 | GEO

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