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dc.contributor.authorAhmad, Zaien_UK
dc.contributor.authorJasnos, Lukaszen_UK
dc.contributor.authorGil, Veronicaen_UK
dc.contributor.authorHowell, Louiseen_UK
dc.contributor.authorHallsworth, Alberten_UK
dc.contributor.authorPetrie, Kevinen_UK
dc.contributor.authorSawado, Tomoyukien_UK
dc.contributor.authorChesler, Louisen_UK
dc.description.abstractMedulloblastoma (MB) is the most common malignant pediatric brain tumor. While the pathways that are deregulated in MB remain to be fully characterized, amplification and/or overexpression of theMYCNgene, which is has a critical role in cerebellar development as a regulator of neural progenitor cell fate, has been identified in several MB subgroups. Phenotypically, aberrant expression of MYCN is associated with the large-cell/anaplastic MB variant, which accounts for 5-15% of cases and is associated with aggressive disease and poor clinical outcome. To better understand the role of MYCN in MBin vitroandin vivoand to aid the development of MYCN-targeted therapeutics we established tumor-derived neurosphere cell lines from the GTML (Glt1-tTA/TRE-MYCN-Luc) genetically engineered mouse model. A fraction of GTML neurospheres were found to be growth factor independent, expressed CD133 (a marker of neural stem cells), failed to differentiate upon MYCN withdrawal and were highly tumorigenic when orthotopically implanted into the cerebellum. Principal component analyzes using single cell RNA assay data suggested that the clinical candidate aurora-A kinase inhibitor MLN8237 converts GTML neurospheres to resemble non-MYCN expressors. Correlating with this, MLN8237 significantly extended the survival of mice bearing GTML MB allografts. In summary, our results demonstrate that MYCN plays a critical role in expansion and survival of aggressive MB-propagating cells, and establish GTML neurospheres as an important resource for the development of novel therapeutic strategies.en_UK
dc.publisherPublic Library of Scienceen_UK
dc.relationAhmad Z, Jasnos L, Gil V, Howell L, Hallsworth A, Petrie K, Sawado T & Chesler L (2015) Molecular and in vivo characterization of cancer-propagating cells derived from MYCN-dependent medulloblastoma. PLoS ONE, 10 (3), Art. No.: e0119834.
dc.rights© 2015 Ahmad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_UK
dc.titleMolecular and in vivo characterization of cancer-propagating cells derived from MYCN-dependent medulloblastomaen_UK
dc.typeJournal Articleen_UK
dc.citation.jtitlePLoS ONEen_UK
dc.type.statusVoR - Version of Recorden_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
dc.contributor.affiliationBiological and Environmental Sciencesen_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
rioxxterms.apcnot requireden_UK
rioxxterms.typeJournal Article/Reviewen_UK
local.rioxx.authorAhmad, Zai|en_UK
local.rioxx.authorJasnos, Lukasz|en_UK
local.rioxx.authorGil, Veronica|en_UK
local.rioxx.authorHowell, Louise|en_UK
local.rioxx.authorHallsworth, Albert|en_UK
local.rioxx.authorPetrie, Kevin|0000-0002-9805-9152en_UK
local.rioxx.authorSawado, Tomoyuki|en_UK
local.rioxx.authorChesler, Louis|en_UK
local.rioxx.projectInternal Project|University of Stirling|
Appears in Collections:Biological and Environmental Sciences Journal Articles

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