Gene expression data from zebrafish SHH medulloblastoma brains and normal brains.
Ontology highlight
ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE242897 | GEO | 2024/07/09
REPOSITORIES: GEO
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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.
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Project description:Germline loss-of-function (LOF) variants in Elongator complex protein 1 (ELP1) are the most prevalent predisposing genetic events in childhood medulloblastoma (MB), accounting for ~30% of the Sonic Hedgehog (SHH) 3 subtype. The underlying mechanism(s) by which germline ELP1 deficiency provokes SHH-MB pathogenesis remain unknown. Genetically engineered mice mimicking heterozygous Elp1 LOF (Elp1HET) seen in affected germline carriers exhibit hallmark features of cancer predisposition in cerebellar granule neuron progenitors (GNPs), including increased DNA replication stress, genomic instability, accelerated cell cycle, and stalled differentiation. Orthotopic transplantation of Elp1HET GNPs harboring somatic Ptch1 inactivation yielded SHH-MB-like tumors with compromised p53 signaling, providing an explanation for the exclusivity of ELP1-associated tumors in SHH-3. Preclinical treatment of ELP1-mutant patient-derived xenografts with an FDA-approved MDM2 inhibitor reactivated p53-dependent apoptosis and extended survival. Our findings functionally substantiate the role of ELP1 deficiency in SHH-MB predisposition and nominate therapeutics that overcome p53 inhibition as a rational treatment option.
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Project description:Medulloblastoma (MB) is a rare disease in adults. In this study we elucidated the genetic landscape and prognostic impact of genetic aberrations in a cohort of 117 adult medulloblastomas. Histological features and pathway activation were evaluated on the protein level; 14.5% showed WNT activation, 63.3% SHH activation and 22.2% were annotated to non-WNT/non-SHH-MB. Genome-wide copy number analysis was performed by molecular inversion probe array technology. MB-related genes were sequenced in WNT- and SHH-activated MBs. 79.7% of SHH-MBs showed desmoplastic/nodular, all other MBs classic histology. WNT-MBs carried oncogenic CTNNB1 mutations in 88.2% and had monosomy 6 in 52.9%. In SHH-MBs, TERT promoter mutations occurred in 97%, mutations in PTCH1 in 38.2%, SMO in 15.5%, SUFU in 7.4%, and TP53-mutations in 4.1%. 84.6% of non-WNT/non-SHH-MBs had an isochromosome 17q. A whole chromosomal aberration (WCA) signature was present in 45.1% of SHH-TP53wt-MBs and 65.4% of non-WNT/non-SHH-MBs. In 98 cases with survival data, WNT-MBs had a 5-year overall survival (OS) of 68.6%. SHH-MBs TP53-wild-type and non-WNT/non-SHH-MBs showed 5-year OS of 80.4% and 70.8%, respectively. TP53-mutant SHH-MBs represented a prognostically unfavorable entity; all patients died within 5 years. Patients with a WCA signature showed significantly increased OS (p-=-0.011 for SHH-TP53wt-MBs, p-=-0.048 for non-WNT/non-SHH-MBs).
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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.
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Project description:Artiodactyls display skeletal adaptations for cursorial (running) locomotion. In these animals, the distal limb skeleton is symmetric, which facilitates walking on the tips of the two central digits, while lateral digits are reduced or lost. We have identified that one primary molecular alteration during the formation of the bovine limb is that, in contrast to mouse, the posterior limb bud mesenchyme does not upregulate Ptch1 expression in response to SHH. We have tracked down this dissimilarity to a cis-regulatory SHH-responsive element that is functionally altered in bovine and established a causal link between lack of upregulation of Ptch1 and acquisition of a symmetric distal autopod. A high resolution 4C-seq protocol involving two restriction digests was applied to viewpoint in Ptch1 promoter (mm9 chr13:63,667,995-63,669,157) in three different tissues, allowing robust detection of physical interactions between regulatory DNA elements.
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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:Artiodactyls display skeletal adaptations for cursorial (running) locomotion. In these animals, the distal limb skeleton is symmetric, which facilitates walking on the tips of the two central digits, while lateral digits are reduced or lost. We have identified that one primary molecular alteration during the formation of the bovine limb is that, in contrast to mouse, the posterior limb bud mesenchyme does not upregulate Ptch1 expression in response to SHH. We have tracked down this dissimilarity to a cis-regulatory SHH-responsive element that is functionally altered in bovine and established a causal link between lack of upregulation of Ptch1 and acquisition of a symmetric distal autopod.
2014-06-19 | GSE52988 | GEO
Project description:Medulloblastoma is the most common malignant brain tumor in children. Here we describe a medulloblastoma model using iPS cell-derived human neuroepithelial stem (NES) cells generated from a Gorlin syndrome patient carrying a germline mutation in the Sonic hedgehog (SHH) receptor PTCH1. We found that Gorlin NES cells formed tumors in mouse cerebellum mimicking human medulloblastoma. Re-transplantation of tumor-isolated NES (tNES) cells resulted in accelerated tumor formation, cells with reduced growth factor dependency, enhanced neurosphere formation in vitro, and increased sensitivity to Vismodegib. Using our model we identified LGALS1 to be a GLI target gene that is upregulated in both Gorlin tNES cells and SHH-subgroup of medulloblastoma patients. Taken together, we demonstrate that NES cells derived from Gorlin patients can be used as a resource to model medulloblastoma initiation and progression, and to identify novel putative targets.
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Project description:The main cell of origin of the Sonic hedgehog (SHH) subgroup of medulloblastoma (MB) is granule cell precursors (GCPs), a SHH-dependent transient amplifying population in the developing cerebellum. SHH-MBs can be further subdivided based on molecular and clinical parameters, as well as location since SHH-MBs occur preferentially in the lateral cerebellum (hemispheres). Our analysis of adult patient data suggests that tumors with Smoothened (SMO) mutations form more specifically in the hemispheres than those with Patched 1 (PTCH1) mutations. Using sporadic mouse models of SHH-MB with the two mutations commonly seen in adult MB, constitutive activation of Smo (SmoM2) or loss-of-Ptch1, we found that regardless of timing of induction or type of mutation, tumors developed primarily in the hemispheres with SmoM2-mutants indeed showing a stronger specificity. We further uncovered that GCPs in the hemispheres are more susceptible to high level SHH signaling compared to GCPs in the medial cerebellum (vermis), as more SmoM2 or Ptch1-mutant hemisphere cells remain undifferentiated and show increased tumorigenicity when transplanted. Finally, we identified location-specific GCP gene expression profiles, and found that deletion of the genes most highly expressed in the hemispheres (Nr2f2) or vermis (Engrailed1) showed opposing effects on GCP differentiation. Our studies thus provide new insights into intrinsic differences within GCPs that impact on SHH-MB progression.
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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.
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