Project description:Classification of medulloblastoma xengrafts models primary human patient medulloblastoma samples were implanted into the corresponding position in SCID mice, the subsequent tumors gene expression profiles were compared with those of primary tumor samples to see if the overall transcriptomes were preserved. Repeat of each sample was the same labeled aRNA loaded onto another chip. Control samples include normal fetal brain, and normal adult cerebellum.
Project description:While international consensus and the 2021 WHO classification recognize multiple molecular medulloblastoma subgroups, these are difficult to identify in current clinical practice. As a result, biology driven risk stratification and therapy assignment for medulloblastoma constitutes a major challenge. Here, we report mass spectrometry analysis of clinical samples as a method for medulloblastoma subgroup discovery and identify MYC immunohistochemistry (IHC) as a clinically tractable method for improved risk stratification.
Project description:While medulloblastoma, a pediatric tumor of the cerebellum, is characterized by aberrations in developmental pathways, the majority of genetic determinants remain unknown. An unbiased Sleeping Beauty transposon screen revealed MyoD as a putative medulloblastoma tumor suppressor. This was unexpected, as MyoD is a muscle differentiation factor and not previously known to be expressed in cerebellum or medulloblastoma. In response to deletion of one allele of MyoD, two other Sonic hedgehog-driven mouse medulloblastoma models showed accelerated tumor formation and death, confirming MyoD as a tumor suppressor in these models. In normal cerebellum, MyoD was expressed in the proliferating granule neuron progenitors that are thought to be precursors to medulloblastoma. Similar to some other tumor suppressors that are induced in cancer, MyoD was expressed in proliferating medulloblastoma cells in three mouse models and in human medulloblastoma cases. This suggests that although expression of MyoD in a proliferating tumor is insufficient to prevent tumor progression, its expression in the cerebellum hinders medulloblastoma genesis. The goal of the gene expression analysis was to determine whether the canonical myogenic differentiation program was involved in increased tumorigenicity following loss of MyoD in the SHH-driven mouse models of medulloblastoma. We compared MyoD+/+; SmoA2 (n=3) with MyoD+/- ;SmoA2 mouse medulloblastoma tumors (n=2).
Project description:To identify molecular subtypes of medulloblastoma we have profiled a series of 62 medulloblastoma tumors. Unsupervised hierarchical cluster analysis of these data identified 5 distinct molecular subtypes. Manuscript submitted. Title: Identification of medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. Authors: Marcel Kool, Jan Koster, Jens Bunt, Nancy E. Hasselt, Arjan Lakeman, Peter van Sluis, Dirk Troost, Netteke Schouten â van Meeteren, Huib N. Caron, Alan MrÅ¡iÄ, Bauke Ylstra, Wieslawa Grajkowska, Wolfgang Hartmann, Torsten Pietsch, David Ellison, Steven C. Clifford, Rogier Versteeg. Keywords: tumor classification 62 human medulloblastoma samples were analzyed
Project description:Molecular classification of medulloblastoma is critical for the correct treatment of this malignant paediatric brain tumour. The analysis of genome-wide DNA methylation patterns has profoundly improved diagnostic precision and classification of brain tumours. However, the implementation of DNA methylation microarrays in daily clinical practice can be time-consuming, costly and inaccessible for many centres worldwide. We aimed to develop a machine-learning decision support system for rapid and cost-effective prediction of medulloblastoma methylation class directly from quantitative PCR data.
Project description:We examined the transformation susceptibility of different cerebellar stem/progenitors by developing several new Group3 medulloblastoma murine models using orthotopic transplantation and in utero electroporation (EP)-based in vivo gene transfer with Cre/LoxP-mediated conditional Myc gene activation and loss of Trp53 function. We used microarrays to compared the transcriptome of these novel Group3 medulloblastoma mouse models and CPC mouse models to existing mouse models of medulloblastoma subgroups and used cross-species analysis to compare these models to human medulloblastoma subgroups
Project description:To identify molecular subtypes of medulloblastoma we have profiled a series of 62 medulloblastoma tumors. Unsupervised hierarchical cluster analysis of these data identified 5 distinct molecular subtypes. Manuscript submitted. Title: Identification of medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. Authors: Marcel Kool, Jan Koster, Jens Bunt, Nancy E. Hasselt, Arjan Lakeman, Peter van Sluis, Dirk Troost, Netteke Schouten – van Meeteren, Huib N. Caron, Alan Mršić, Bauke Ylstra, Wieslawa Grajkowska, Wolfgang Hartmann, Torsten Pietsch, David Ellison, Steven C. Clifford, Rogier Versteeg. Keywords: tumor classification
Project description:The childhood brain tumour medulloblastoma includes four subtypes with very different prognoses. Here, we show that paracrine signals driven by mutant Beta-Catenin in WNT-medulloblastoma â an essentially curable form of the disease â induce an aberrant fenestrated vasculature that permits the accumulation of high levels of intra-tumoural chemotherapy and a robust therapeutic response. In contrast, SHH-medulloblastoma â a less curable disease subtype â contains an intact blood brain barrier, rendering this tumour impermeable and resistant to chemotherapy. Remarkably, the medulloblastoma-endothelial cell paracrine axis can be manipulated in vivo, altering chemotherapy permeability and clinical response. Thus, medulloblastoma genotype dictates tumour vessel phenotype, explaining in part the disparate prognoses among medulloblastoma subtypes and suggesting an approach to enhance the chemoresponsiveness of other brain tumours. We used microarrays to detail the global program of gene expression within endothelial cells from normal mouse hindbrain and genetic mouse models of different medulloblastoma subtypes to identify and verify up-regulated and down-regulated genes Endothelial cells were isolated from adult mouse hindbrain and genetic mouse models of Wnt and Shh-medulloblastoma using Cd-144 and Cd-105 antibodies based magnetic sorting. RNA was extracted and used for hybridization on Affymetrix microarrays. We sought to identify changes in endothelial gene expression patterns based on the surrounding microenvironment, so we purified endothelial cells from normal mouse brain or tumors from genetic mouse models. These include the Shh-medulloblastoma model (Ptch+/-; Ink4c -/-) and Wnt-medulloblastoma model (Blbp-Cre; mutant Ctnnb1+/-; p53-/-; mutant Pik3ca +/-)
Project description:While medulloblastoma, a pediatric tumor of the cerebellum, is characterized by aberrations in developmental pathways, the majority of genetic determinants remain unknown. An unbiased Sleeping Beauty transposon screen revealed MyoD as a putative medulloblastoma tumor suppressor. This was unexpected, as MyoD is a muscle differentiation factor and not previously known to be expressed in cerebellum or medulloblastoma. In response to deletion of one allele of MyoD, two other Sonic hedgehog-driven mouse medulloblastoma models showed accelerated tumor formation and death, confirming MyoD as a tumor suppressor in these models. In normal cerebellum, MyoD was expressed in the proliferating granule neuron progenitors that are thought to be precursors to medulloblastoma. Similar to some other tumor suppressors that are induced in cancer, MyoD was expressed in proliferating medulloblastoma cells in three mouse models and in human medulloblastoma cases. This suggests that although expression of MyoD in a proliferating tumor is insufficient to prevent tumor progression, its expression in the cerebellum hinders medulloblastoma genesis.