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Cryptic developmental events determine medulloblastoma radiosensitivity and cellular heterogeneity without altering transcriptomic profile

ABSTRACT: Cryptic developmental events determine medulloblastoma radiosensitivity and cellular heterogeneity without altering transcriptomic profile

PROVIDER: PRJNA632849 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11790209_1.fastq.gz	Fastqsanger.gz
	SRR11790209_2.fastq.gz	Fastqsanger.gz
	SRR11790210_1.fastq.gz	Fastqsanger.gz
	SRR11790210_2.fastq.gz	Fastqsanger.gz
	SRR11790211_1.fastq.gz	Fastqsanger.gz

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Cryptic developmental events determine medulloblastoma radiosensitivity and cellular heterogeneity without altering transcriptomic profile

Project description:Using scRNA-seq, we show in a murine medulloblastoma model that tumors initiated earlier in development differ from later initiated tumors in their cellular composition and response to radiation therapy.

2020-05-15 | GSE150579 | GEO

Cryptic developmental events determine medulloblastoma radiosensitivity and cellular heterogeneity without altering transcriptomic profile.

Project description:It is unclear why medulloblastoma patients receiving similar treatments experience different outcomes. Transcriptomic profiling identified subgroups with different prognoses, but in each subgroup, individuals remain at risk of incurable recurrence. To investigate why similar-appearing tumors produce variable outcomes, we analyzed medulloblastomas triggered in transgenic mice by a common driver mutation expressed at different points in brain development. We genetically engineered mice to express oncogenic SmoM2, starting in multipotent glio-neuronal stem cells, or committed neural progenitors. Both groups developed medulloblastomas with similar transcriptomic profiles. We compared medulloblastoma progression, radiosensitivity, and cellular heterogeneity, determined by single-cell transcriptomic analysis (scRNA-seq). Stem cell-triggered medulloblastomas progressed faster, contained more OLIG2-expressing stem-like cells, and consistently showed radioresistance. In contrast, progenitor-triggered MBs progressed slower, down-regulated stem-like cells and were curable with radiation. Progenitor-triggered medulloblastomas also contained more diverse stromal populations, with more Ccr2+ macrophages and fewer Igf1+ microglia, indicating that developmental events affected the subsequent tumor microenvironment. Reduced mTORC1 activity in M-Smo tumors suggests that differential Igf1 contributed to differences in phenotype. Developmental events in tumorigenesis that were obscure in transcriptomic profiles thus remained cryptic determinants of tumor composition and outcome. Precise understanding of medulloblastoma pathogenesis and prognosis requires supplementing transcriptomic/methylomic studies with analyses that resolve cellular heterogeneity.

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PRDM6 promotes medulloblastoma by repressing chromatin accessibility and altering gene expression

Project description:PRDM6 promotes medulloblastoma by repressing chromatin accessibility and altering gene expression

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Expression data of endothelial cells from mouse hindbrain and genetic Wnt-medulloblastoma and Shh-medulloblastoma mouse models

Project description:The childhood brain tumour medulloblastoma includes four subtypes with very different prognoses. Here, we show that paracrine signals driven by mutant Beta-Catenin in WNT-medulloblastoma â an essentially curable form of the disease â induce an aberrant fenestrated vasculature that permits the accumulation of high levels of intra-tumoural chemotherapy and a robust therapeutic response. In contrast, SHH-medulloblastoma â a less curable disease subtype â contains an intact blood brain barrier, rendering this tumour impermeable and resistant to chemotherapy. Remarkably, the medulloblastoma-endothelial cell paracrine axis can be manipulated in vivo, altering chemotherapy permeability and clinical response. Thus, medulloblastoma genotype dictates tumour vessel phenotype, explaining in part the disparate prognoses among medulloblastoma subtypes and suggesting an approach to enhance the chemoresponsiveness of other brain tumours. We used microarrays to detail the global program of gene expression within endothelial cells from normal mouse hindbrain and genetic mouse models of different medulloblastoma subtypes to identify and verify up-regulated and down-regulated genes Endothelial cells were isolated from adult mouse hindbrain and genetic mouse models of Wnt and Shh-medulloblastoma using Cd-144 and Cd-105 antibodies based magnetic sorting. RNA was extracted and used for hybridization on Affymetrix microarrays. We sought to identify changes in endothelial gene expression patterns based on the surrounding microenvironment, so we purified endothelial cells from normal mouse brain or tumors from genetic mouse models. These include the Shh-medulloblastoma model (Ptch+/-; Ink4c -/-) and Wnt-medulloblastoma model (Blbp-Cre; mutant Ctnnb1+/-; p53-/-; mutant Pik3ca +/-)

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PRDM6 promotes medulloblastoma by repressing chromatin accessibility and altering gene expression [CUT&Run]

Project description:PRDM6 promotes medulloblastoma by repressing chromatin accessibility and altering gene expression [CUT&Run]

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PRDM6 promotes medulloblastoma by repressing chromatin accessibility and altering gene expression [RNA-Seq]

Project description:PRDM6 promotes medulloblastoma by repressing chromatin accessibility and altering gene expression [RNA-Seq]

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PRDM6 promotes medulloblastoma by repressing chromatin accessibility and altering gene expression [ATAC-Seq]

Project description:PRDM6 promotes medulloblastoma by repressing chromatin accessibility and altering gene expression [ATAC-Seq]

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PRDM6 promotes medulloblastoma by repressing chromatin accessibility and altering gene expression [CUT&Run]

Project description:SNCAIP duplication may promote Group 4 medulloblastoma via induction of PRDM6, a poorly characterized member of the PRDF1 and RIZ1 homology domain-containing (PRDM) family of transcription factors. Here, we investigated the function of PRDM6 in human hindbrain neuroepithelial stem cells and tested PRDM6 as a driver of Group 4 medulloblastoma. We report that human PRDM6 localizes predominantly to the nucleus, where it causes widespread repression of chromatin accessibility and complex alterations of gene expression patterns. Genome-wide mapping of PRDM6 binding reveals that PRDM6 binds to chromatin regions marked by histone H3 lysine 27 trimethylation that are located within, or proximal to, genes. Moreover, we show that PRDM6 expression in neuroepithelial stem cells promotes medulloblastoma. Surprisingly, medulloblastomas derived from PRDM6-expressing neuroepithelial stem cells match human Group 3, but not Group 4, medulloblastoma. We conclude that PRDM6 expression has oncogenic potential but is insufficient to drive Group 4 medulloblastoma from neuroepithelial stem cells. We propose that both PRDM6 and additional factors, such as specific cell-of-origin features, are required for Group 4 medulloblastoma. Given the lack of PRDM6 expression in normal tissues and its oncogenic potential shown here, we suggest that PRDM6 inhibition may have therapeutic value in PRDM6-expressing medulloblastomas.

2024-07-17 | GSE243557 | GEO

PRDM6 promotes medulloblastoma by repressing chromatin accessibility and altering gene expression [ATAC-Seq]

2024-07-17 | GSE243556 | GEO

PRDM6 promotes medulloblastoma by repressing chromatin accessibility and altering gene expression [RNA-Seq]

2024-07-17 | GSE243554 | GEO