title: Molecular and in vivo characterization of cancer-propagating cells derived from MYCN-dependent medulloblastoma.
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.
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, London, SM2 5NG, United Kingdom.
authors.forename: Zai
authors.initials: Z
authors.lastname: Ahmad
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London, SM2 5NG, United Kingdom.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Jasnos
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, London, SM2 5NG, United Kingdom.
authors.forename: Veronica
authors.initials: V
authors.lastname: Gil
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London, SM2 5NG, United Kingdom.
authors.forename: Louise
authors.initials: L
authors.lastname: Howell
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, London, SM2 5NG, United Kingdom.
authors.forename: Albert
authors.initials: A
authors.lastname: Hallsworth
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, London, SM2 5NG, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Petrie
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London, SM2 5NG, United Kingdom.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Sawado
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, London, SM2 5NG, United Kingdom.
authors.forename: Louis
authors.initials: L
authors.lastname: Chesler
mesh_terms: D064591:Allografts; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D000071447:N-Myc Proto-Oncogene Protein; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D025341:Principal Component Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; C550258:MLN 8237; C571825:MYCN protein, mouse; D000071447:N-Myc Proto-Oncogene Protein; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; C576918:Aurka protein, mouse; D064096:Aurora Kinase A