Determining the chromatin accessibility profiles of functionally distinct SHH-medulloblastoma sub-populations
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE233993 | GEO | 2024/09/11
REPOSITORIES: GEO
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Project description:Determining the chromatin accessibility profiles of functionally distinct SHH-medulloblastoma sub-populations
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Project description:Zebrafish SHH MB tumors were generated by CRISPR-Cas9-mediated mutation of ptch1 in the context of tp53 heterozygous and tp53 mutant animals. Gene expression of the entire brain for ptch1 crispant animals and tp53 mutant control animals was analyzed by RNA-seq.
2024-07-09 | GSE242897 | GEO
Project description:The identification of Lgr5 as an intestinal stem cell marker has made it possible to isolate and study primary stem cells from small intestine. Using the cell cycle specific expression og the mKi67 gene, we generated a novel Ki67-RFP knock-in allele which identifies dividing cells. Using Lgr5-GFP;Ki67-RFP mice, we isolated CBCs with distinct Wnt signaling levels and cell cycle features, and analyzed their global gene expression pattern using microarrays. We concluded that the cycling Lgr5hi stem cells exit the cell cycle in transition into the secretory lineage. Lgr5med Ki67low intermediate precursors reside in the zone of differentiation, resemble quiescent stem cells and generate the Dll1+ secretory precursors and the label retaining cells. Our findings support the cycling stem cell hypothesis and highlight the heterogeneity of early progenitors during lineage commitment. We used cell fractions of intestines from Lgr5-EGFP-ires-CreERT2 mice, expressing GFP under the control of the Lgr5 promoter, and Ki67-TagRFP mice where the RFP is fused to the C-terminus of the endogenous Ki67 gene. RNA was isolated from several FACS sorted cell populations of combinations expressing different levels of GFP and RFP: GFP high RFP high (Lgr5hi Ki67hi), GFP high RFP low (Lgr5hi Ki67low), GFP medium RFP high (Lgr5med Ki67high) and GFP medium RFP low (Lgr5med Ki67low). Purified RNA was processed, hybridized, and scanned according to the manufacturerM-bM-^@M-^Ys protocol and were hybridized on Affymetrix Mouse Gene ST 1.1 arrays).
2014-09-08 | E-GEOD-52813 | biostudies-arrayexpress
Project description:The identification of Lgr5 as an intestinal stem cell marker has made it possible to isolate and study primary stem cells from small intestine. Using the cell cycle specific expression og the mKi67 gene, we generated a novel Ki67-RFP knock-in allele which identifies dividing cells. Using Lgr5-GFP;Ki67-RFP mice, we isolated CBCs with distinct Wnt signaling levels and cell cycle features, and analyzed their global gene expression pattern using microarrays. We concluded that the cycling Lgr5hi stem cells exit the cell cycle in transition into the secretory lineage. Lgr5med Ki67low intermediate precursors reside in the zone of differentiation, resemble quiescent stem cells and generate the Dll1+ secretory precursors and the label retaining cells. Our findings support the cycling stem cell hypothesis and highlight the heterogeneity of early progenitors during lineage commitment.
2014-09-08 | GSE52813 | GEO
Project description:Aberrant activation of the Hedgehog (Hh) signaling pathway is implicated in the pathogenesis of many cancers, including medulloblastoma and basal cell carcinoma (BCC). In this study, using neonatally irradiated Ptch1+/- mice as a model of Hh-dependent tumors, we investigated the in vivo effects of MK-4101, a novel SMO antagonist, for treatment of medulloblastoma and BCC. Results clearly demonstrate a robust antitumor activity of MK-4101, achieved through the inhibition of proliferation and induction of extensive apoptosis in tumor cells. Of note, beside antitumor activity on transplanted tumors, MK-4101 was highly efficacious against primary medulloblastoma and BCC developing in the cerebellum and skin of Ptch1+/- mice. By identifying the changes induced by MK-4101 in gene expression profiles in tumors, we also elucidate the mechanism of action of this novel, orally administrable compound. MK-4101 targets the Hh pathway in the tumor cells, showing the maximum inhibitory effect on Gli1 activity. MK-4101 also induced deregulation of cell cycle and block of DNA replication in tumors. Members of the IGF and Wnt signaling pathways , were among the most highly deregulated genes by MK-4101, suggesting that the interplay among Hh, IGF and Wnt is crucial in Hh-dependent tumorigenesis. Altogether, the results of this preclinical study support a therapeutic opportunity for MK-4101 in the treatment of Hh-driven cancers, also providing useful information for combination therapy with drugs targeting pathways cooperating with Hh oncogenic activity. Gene expression data was generated (in replicates) from Medulloblastoma allografts collected at various time points and following low (40mpk) or high (80 mpk) or vehicle single dose (QD) or mutiple dose (BID) treatment with a SHH pathway inhibitor.
2016-03-14 | E-GEOD-77042 | biostudies-arrayexpress
Project description:SUFU alterations are commonly detected in human SHH subgroup of medulloblastoma. Here we profile the gene expression of P13 wildtype and Sufu KO cerebellum, as well as Ptch1 KO MB in biological triplicate.
2018-12-13 | GSE112699 | GEO
Project description:Medulloblastoma (MB) is the most prevalent pediatric cerebral cancer, but is rare in adults. The vast majority of MB arises sporadically but some few cases occur in association with germline alterations in genes such as PTCH1, SUFU, APC, and TP53. Additional genes are responsible for MB predisposition including some that have probably not been described so far either due to the rarity of the cases and/or to the low penetrance. Here we report the case of a 27 years old woman affected by Pitt Hopkins syndrome due to a heterozygous germline pathogenic variant in TCF4 who has developed a Sonic Hedgehog (SHH)-driven MB. Somatic loss of function variants of TCF4 have been identified in SHH MB especially among adults and this case raises the question of a predisposition to late-onset SHH MB associated with TCF4 germline alteration.
2019-02-14 | GSE126545 | GEO
Project description:Aberrant activation of the Hedgehog (Hh) signaling pathway is implicated in the pathogenesis of many cancers, including medulloblastoma and basal cell carcinoma (BCC). In this study, using neonatally irradiated Ptch1+/- mice as a model of Hh-dependent tumors, we investigated the in vivo effects of MK-4101, a novel SMO antagonist, for treatment of medulloblastoma and BCC. Results clearly demonstrate a robust antitumor activity of MK-4101, achieved through the inhibition of proliferation and induction of extensive apoptosis in tumor cells. Of note, beside antitumor activity on transplanted tumors, MK-4101 was highly efficacious against primary medulloblastoma and BCC developing in the cerebellum and skin of Ptch1+/- mice. By identifying the changes induced by MK-4101 in gene expression profiles in tumors, we also elucidate the mechanism of action of this novel, orally administrable compound. MK-4101 targets the Hh pathway in the tumor cells, showing the maximum inhibitory effect on Gli1 activity. MK-4101 also induced deregulation of cell cycle and block of DNA replication in tumors. Members of the IGF and Wnt signaling pathways , were among the most highly deregulated genes by MK-4101, suggesting that the interplay among Hh, IGF and Wnt is crucial in Hh-dependent tumorigenesis. Altogether, the results of this preclinical study support a therapeutic opportunity for MK-4101 in the treatment of Hh-driven cancers, also providing useful information for combination therapy with drugs targeting pathways cooperating with Hh oncogenic activity.
2016-03-14 | GSE77042 | GEO
Project description:Many genes that drive normal cellular development also contribute to oncogenesis. Medulloblastoma (MB) tumors likely arise from neuronal progenitors in the cerebellum, and we hypothesized that the heterogeneity observed in MBs with sonic hedgehog (SHH) activation could be due to differences in developmental pathways. To investigate this question, here we perform single-nucleus RNA sequencing on highly differentiated SHH MBs with extensively nodular histology and observed malignant cells resembling each stage of canonical granule neuron development. Through innovative computational approaches, we connect these results to published datasets and find that some established molecular subtypes of SHH MB appear arrested at different developmental stages. Additionally, using multiplexed proteomic imaging and MALDI imaging mass spectrometry, we identify distinct histological and metabolic profiles for highly differentiated tumors. Our approaches are applicable to understanding the interplay between heterogeneity and differentiation in other cancers and can provide important insights for the design of targeted therapies.
| S-EPMC10774283 | biostudies-literature
Project description:Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.
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