CD271/p75NTR is a novel diagnostic marker, prognostic indicator and therapeutic target in SHH medulloblastoma
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PROVIDER: PRJNA421151 | ENA |
REPOSITORIES: ENA
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Project description:The extensive heterogeneity both between and within the medulloblastoma (MB) subgroups underscores a critical need for variant-specific biomarkers and therapeutic strategies. We previously identified a role for the CD271/p75 neurotrophin receptor (p75NTR) in regulating stem/progenitor cells in the SHH MB subgroup. Here, we demonstrate the utility of CD271 as a novel diagnostic and prognostic marker for SHH MB using immunohistochemical analysis as well as transcriptome data across 763 primary tumors. Characterization of CD271+ and CD271- cells by RNA sequencing revealed that these two subpopulations are molecularly distinct, co-existing cellular subsets both in vitro and in vivo. MAPK/ERK signaling is upregulated in the CD271+ population and inhibiting this pathway reduced CD271 levels, stem/progenitor cell proliferation and cell survival as well as cell migration in vitro. Importantly, the MEK inhibitor selumetinib extends survival and reduces CD271 levels in vivo. Our study demonstrates the clinical utility of CD271 as both a diagnostic and prognostic tool for SHH MB tumors and reveals a novel role for MEK inhibitors in targeting CD271+ SHH MB cells.
2019-12-31 | GSE107701 | GEO
Project description:Sequencing data of human SHH medulloblastoma samples
| EGAS00001000607 | EGA
Project description:Differences in gene expression between unsorted adipose tissue-derived mesenchymal stem cells (AD-MSCs), and a specific subpopulation that has been selected for the expression of the surface marker CD271. It is believed that the selection of this specific subpopulation from the heterogeneous SVF will lead to mesenchymal stem cells with higher angiogenetic potential.
2021-01-27 | E-MTAB-8740 | biostudies-arrayexpress
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
Project description:Single-Nucleus RNA-Sequencing and Single-Cell RNA-Sequencing from SHH Medulloblastoma Tumors with MBEN histology
2023-11-21 | GSE214469 | GEO
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).
2021-02-24 | GSE167347 | GEO
Project description:Analyze and compare the gene expression profile of human bone marrow primary CD45-CD271+ and CD45-CD271- cells. The hypothesis was some genes were differentially expressed in these two populations. Results provided important information regarding the gene expression difference of these two cell populations.
2015-03-17 | GSE57927 | GEO
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
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
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