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Modeling Pediatric Medulloblastoma.

Published on May 1, 2020in Brain Pathology6.352
· DOI :10.1111/BPA.12803
Martine F. Roussel79
Estimated H-index: 79
(St. Jude Children's Research Hospital),
Jennifer Stripay1
Estimated H-index: 1
(St. Jude Children's Research Hospital)
Abstract
Mouse models of medulloblastoma have proven to be instrumental in understanding disease mechanisms, particularly the role of epigenetic and molecular drivers, and establishing appropriate preclinical pipelines. To date, our research community has developed murine models for all four groups of medulloblastoma, each of which will be critical for the identification and development of new therapeutic approaches. Approaches to modeling medulloblastoma range from genetic engineering with CRISPR/Cas9 or in utero electroporation, to orthotopic and patient-derived orthotopic xenograft systems. Each approach or model presents unique advantages that have ultimately contributed to an appreciation of medulloblastoma heterogeneity and the clinical obstacles that exist for this patient population.
  • References (79)
  • Citations (2)
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References79
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#1Miller Huang (UCSF: University of California, San Francisco)H-Index: 6
#2Jignesh TailorH-Index: 2
Last. William A. Weiss (UCSF: University of California, San Francisco)H-Index: 61
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Summary Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here, we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN , observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methy...
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#1Volker Hovestadt (Broad Institute)H-Index: 39
#2Kyle S Smith (St. Jude Children's Research Hospital)H-Index: 3
Last. Paul A. Northcott (St. Jude Children's Research Hospital)H-Index: 63
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Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup...
6 CitationsSource
#1Pauline J. Beckmann (UMN: University of Minnesota)H-Index: 2
#2Jon D. Larson (UMN: University of Minnesota)H-Index: 13
Last. David A. Largaespada (UMN: University of Minnesota)H-Index: 51
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Medulloblastoma and central nervous system primitive neuroectodermal tumors (CNS-PNET) are aggressive, poorly differentiated brain tumors with limited effective therapies. Using Sleeping Beauty (SB) transposon mutagenesis, we identified novel genetic drivers of medulloblastoma and CNS-PNET. Cross-species gene expression analyses classified SB-driven tumors into distinct medulloblastoma and CNS-PNET subgroups, indicating they resemble human SHH and group 3 and 4 medulloblastoma and CNS neuroblast...
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#1Cathy Lee (UCSD: University of California, San Diego)H-Index: 9
#2Vasilisa A. Rudneva (St. Jude Children's Research Hospital)H-Index: 4
Last. Robert J. Wechsler-Reya (UCSD: University of California, San Diego)H-Index: 40
view all 17 authors...
Drugs that modify the epigenome are powerful tools for treating cancer, but these drugs often have pleiotropic effects, and identifying patients who will benefit from them remains a major clinical challenge. Here we show that medulloblastomas driven by the transcription factor Gfi1 are exquisitely dependent on the enzyme lysine demethylase 1 (Kdm1a/Lsd1). We demonstrate that Lsd1 physically associates with Gfi1, and that these proteins cooperate to inhibit genes involved in neuronal commitment a...
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#1Jon D. Larson (St. Jude Children's Research Hospital)H-Index: 3
#2Lawryn H. Kasper (St. Jude Children's Research Hospital)H-Index: 20
Last. Suzanne J. Baker (St. Jude Children's Research Hospital)H-Index: 45
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Summary Diffuse intrinsic pontine gliomas (DIPGs) are incurable childhood brainstem tumors with frequent histone H3 K27M mutations and recurrent alterations in PDGFRA and TP53 . We generated genetically engineered inducible mice and showed that H3.3 K27M enhanced neural stem cell self-renewal while preserving regional identity. Neonatal induction of H3.3 K27M cooperated with activating platelet-derived growth factor receptor α (PDGFRα) mutant and Trp53 loss to accelerate development of diffuse b...
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#1Sebastian Brabetz (DKFZ: German Cancer Research Center)H-Index: 10
#2Sarah Leary (UW: University of Washington)H-Index: 14
Last. James M. Olson (UW: University of Washington)H-Index: 58
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Brain tumors are the leading cause of cancer-related death in children. Genomic studies have provided insights into molecular subgroups and oncogenic drivers of pediatric brain tumors that may lead to novel therapeutic strategies. To evaluate new treatments, better preclinical models adequately reflecting the biological heterogeneity are needed. Through the Children’s Oncology Group ACNS02B3 study, we have generated and comprehensively characterized 30 patient-derived orthotopic xenograft models...
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#1Antoine Forget (Université Paris-Saclay)H-Index: 3
Last. Olivier Ayrault (Université Paris-Saclay)H-Index: 11
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Summary The current consensus recognizes four main medulloblastoma subgroups (wingless, Sonic hedgehog, group 3 and group 4). While medulloblastoma subgroups have been characterized extensively at the (epi-)genomic and transcriptomic levels, the proteome and phosphoproteome landscape remain to be comprehensively elucidated. Using quantitative (phospho)-proteomics in primary human medulloblastomas, we unravel distinct posttranscriptional regulation leading to highly divergent oncogenic signaling ...
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#1BaoHan T. Vo (St. Jude Children's Research Hospital)H-Index: 1
#2Jin Ah Kwon (St. Jude Children's Research Hospital)
Last. Martine F. Roussel (St. Jude Children's Research Hospital)H-Index: 79
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MYC-driven Group 3 (G3) medulloblastoma (MB) is the most aggressive of four molecular subgroups classified by transcriptome, genomic landscape and clinical outcomes. Mouse models that recapitulate human G3 MB all rely on retroviral vector-induced Myc expression driven by viral regulatory elements (Retro-Myc tumors). We used nuclease-deficient CRISPR/dCas9-based gene activation with combinatorial single guide RNAs (sgRNAs) to enforce transcription of endogenous Myc in Trp53-null neurospheres that...
Source
#1Shilpa S. Dhar (University of Texas MD Anderson Cancer Center)H-Index: 16
#2Dongyu Zhao (Cornell University)H-Index: 3
Last. Min Gyu Lee (University of Texas Health Science Center at Houston)H-Index: 20
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Summary Super-enhancers are large clusters of enhancers that activate gene expression. Broad trimethyl histone H3 lysine 4 (H3K4me3) often defines active tumor suppressor genes. However, how these epigenomic signatures are regulated for tumor suppression is little understood. Here we show that brain-specific knockout of the H3K4 methyltransferase MLL4 (a COMPASS-like enzyme, also known as KMT2D) in mice spontaneously induces medulloblastoma. Mll4 loss upregulates oncogenic Ras and Notch pathways...
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#1David W. Ellison (St. Jude Children's Research Hospital)H-Index: 73
In this mini-symposium, four review articles describe recent advances in our understanding of the pathobiology of medulloblastoma. Medulloblastoma is the commonest malignant brain tumor of childhood and has been the subject of intense scientific investigation over several decades.
Source
#1Jennifer StripayH-Index: 1
#2Thomas E. Merchant (St. Jude Children's Research Hospital)H-Index: 52
Last. Christopher L. TinkleH-Index: 8
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: Medulloblastoma is an embryonal tumor that shows a predilection for distant metastatic spread and leptomeningeal seeding. For most patients, optimal management of medulloblastoma includes maximum safe resection followed by adjuvant craniospinal irradiation (CSI) and chemotherapy. Although CSI is crucial in treating medulloblastoma, the realization that medulloblastoma is a heterogeneous disease comprising four distinct molecular subgroups (wingless [WNT], sonic hedgehog [SHH], Group 3 [G3], an...
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