Medulloblastoma group 3 and 4 tumors comprise a clinically and biologically significant expression continuum reflecting human cerebellar development

Williamson, Daniel; Schwalbe, Ed C.; Hicks, Debbie; Aldinger, Kimberly A.; Lindsey, Janet C.; Crosier, Stephen; Richardson, Stacey; Goddard, Jack; Hill, Rebecca; Castle, Jemma; Grabovska, Yura; Hacking, James; Pizer, Barry; Wharton, Stephen B.; Jacques, Thomas S.; Joshi, Abhijit; Bailey, Simon; Clifford, Steven C

doi:10.1016/j.celrep.2022.111162

Cited by 39 publications

(45 citation statements)

References 61 publications

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“…Consistent with the previously identified associations of the models with Group 3 subsets (Fig. 2f ) and the distinct photoreceptor signature of Group 3 MBs 38 , the observed differential enrichment of the photoreceptor gene set between the models was well recapitulated by corresponding differences between Group 3α and Group 3γ MBs (Fig. 4c ), suggesting again that GTML tumors might be more similar to Group 3α MBs.…”

Section: Resultssupporting

confidence: 89%

ARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors

et al. 2023

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Medulloblastoma, the most common malignant pediatric brain tumor, often harbors MYC amplifications. Compared to high-grade gliomas, MYC-amplified medulloblastomas often show increased photoreceptor activity and arise in the presence of a functional ARF/p53 suppressor pathway. Here, we generate an immunocompetent transgenic mouse model with regulatable MYC that develop clonal tumors that molecularly resemble photoreceptor-positive Group 3 medulloblastoma. Compared to MYCN-expressing brain tumors driven from the same promoter, pronounced ARF silencing is present in our MYC-expressing model and in human medulloblastoma. While partial Arf suppression causes increased malignancy in MYCN-expressing tumors, complete Arf depletion promotes photoreceptor-negative high-grade glioma formation. Computational models and clinical data further identify drugs targeting MYC-driven tumors with a suppressed but functional ARF pathway. We show that the HSP90 inhibitor, Onalespib, significantly targets MYC-driven but not MYCN-driven tumors in an ARF-dependent manner. The treatment increases cell death in synergy with cisplatin and demonstrates potential for targeting MYC-driven medulloblastoma.

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Section: Resultssupporting

confidence: 89%

ARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors

et al. 2023

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“…Data from a recent study using SMART-seq or bulk RNA-seq implied a cell-state continuum among G3 and G4 MBs 4,46 . However, our unbiased single-cell clustering predicted that distinct populations of prototypical G3 and G4 tumor cells are present within G3/G4 tumors as opposed to a spectrum between G3 and G4 tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Human fetal cerebellar cell atlas informs medulloblastoma origin and oncogenesis

Luo

Xia

Wei

et al. 2022

Preprint

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Medulloblastomas (MBs) are the most common malignant childhood brain tumors, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatment strategies. Previous cell-type analyses of mouse cerebella or human counterparts from frozen tissue nuclei have not fully defined the compositional heterogeneity of MBs. Here, we undertook an unprecedented single-cell profiling of freshly-isolated human fetal cerebella at different developmental stages to establish a reference map for delineating the hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in human fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group-3 and metastatic tumors. Integrated single-cell multi-omic profiling revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in aggressive group-3 MBs. Genomic profiling and Hi-C analyses identified de novo long-range chromatin loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group-3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group-3 MB growth. Together, our integrated single-cell atlases of human fetal cerebella and MBs reveal important cell populations predisposed to transformation and regulatory circuitries underlying tumor cell state evolution and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.

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“…Through human single cell RNA sequencing (scRNA-seq) of fetal cerebellar data, the interplay between oncogenic events and putative cells of origin for each MB subtype were mapped (Williamson et al, 2022). In this regard, MB occurs in various neuronal stem or progenitor cell populations according to the consensus subgroup.…”

Section: The Genetic Landscape Of Mb Subtypes and Their Cellular Originsmentioning

confidence: 99%

Epigenetics and immune cells in medulloblastoma

et al. 2023

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Medulloblastoma (MB) is a highly malignant childhood tumor of the cerebellum. Transcriptional and epigenetic signatures have classified MB into four molecular subgroups, further stratified into biologically different subtypes with distinct somatic copy-number aberrations, driver genes, epigenetic alterations, activated pathways, and clinical outcomes. The brain tumor microenvironment (BTME) is of importance to regulate a complex network of cells, including immune cells, involved in cancer progression in brain malignancies. MB was considered with a “cold” immunophenotype due to the low influx of immune cells across the blood brain barrier (BBB). Recently, this assumption has been reconsidered because of the identification of infiltrating immune cells showing immunosuppressive phenotypes in the BTME of MB tumors. Here, we are providing a comprehensive overview of the current status of epigenetics alterations occurring during cancer progression with a description of the genomic landscape of MB by focusing on immune cells within the BTME. We further describe how new immunotherapeutic approaches could influence concurring epigenetic mechanisms of the immunosuppressive cells in BTME. In conclusion, the modulation of these molecular genetic complexes in BTME during cancer progression might enhance the therapeutic benefit, thus firing new weapons to fight MB.

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Medulloblastoma group 3 and 4 tumors comprise a clinically and biologically significant expression continuum reflecting human cerebellar development

Cited by 39 publications

References 61 publications

ARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors

ARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors

Human fetal cerebellar cell atlas informs medulloblastoma origin and oncogenesis

Epigenetics and immune cells in medulloblastoma

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