Molecular and in vivo characterization of cancer-propagating cells derived from MYCN-dependent medulloblastoma.

Ahmad, Zai, Jasnos, Lukasz, Gil, Veronica, Howell, Louise, Hallsworth, Albert, Petrie, Kevin, Sawado, Tomoyuki and Chesler, Louis (2015) Molecular and in vivo characterization of cancer-propagating cells derived from MYCN-dependent medulloblastoma. PloS one, 10 (3). e0119834. ISSN 1932-6203

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Abstract

Medulloblastoma (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 the MYCN gene, 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 MB in vitro and in vivo and 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.

Item Type: Article
Subjects: Sciences > Biomedical Sciences
Sciences > Health Sciences
Divisions: Faculty of Health Sciences and Wellbeing > School of Medicine
Depositing User: Kevin Petrie
Date Deposited: 18 Aug 2020 18:46
Last Modified: 19 Aug 2020 09:39
URI: http://sure.sunderland.ac.uk/id/eprint/12438
ORCID for Kevin Petrie: ORCID iD orcid.org/0000-0002-9805-9152

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