Distinct Neural Stem Cell Populations Give Rise to Disparate Brain Tumors in Response to N-MYC

• Published in: Cancer cell Vol. 21; no. 5; pp. 601 - 613
• Main Authors: Swartling, Fredrik J., Savov, Vasil, Persson, Anders I., Chen, Justin, Hackett, Christopher S., Northcott, Paul A., Grimmer, Matthew R., Lau, Jasmine, Chesler, Louis, Perry, Arie, Phillips, Joanna J., Taylor, Michael D., Weiss, William A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.05.2012
• Subjects: Animals; Biomarkers - metabolism; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Stem - embryology; Brain Stem - metabolism; Cell Differentiation; Cell Lineage; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cerebellar Neoplasms - metabolism; Cerebellar Neoplasms - pathology; Cerebellum - embryology; Cerebellum - metabolism; Female; Gestational Age; Glioma - metabolism; Glioma - pathology; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Humans; Kruppel-Like Transcription Factors - metabolism; Medulloblastoma - metabolism; Medulloblastoma - pathology; Mice; Mice, Nude; Mice, Transgenic; Mutation; N-Myc Proto-Oncogene Protein; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; Neuroectodermal Tumors, Primitive - metabolism; Neuroectodermal Tumors, Primitive - pathology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Prosencephalon - embryology; Prosencephalon - metabolism; Proto-Oncogene Mas; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Signal Transduction; SOX9 Transcription Factor - genetics; SOX9 Transcription Factor - metabolism; Spheroids, Cellular; Time Factors; Transduction, Genetic; Zinc Finger Protein Gli2
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccr.2012.04.012

The proto-oncogene MYCN is mis-expressed in various types of human brain tumors. To clarify how developmental and regional differences influence transformation, we transduced wild-type or mutationally stabilized murine N-mycT58A into neural stem cells (NSCs) from perinatal murine cerebellum, brain stem, and forebrain. Transplantation of N-mycWT NSCs was insufficient for tumor formation. N-mycT58A cerebellar and brain stem NSCs generated medulloblastoma/primitive neuroectodermal tumors, whereas forebrain NSCs developed diffuse glioma. Expression analyses distinguished tumors generated from these different regions, with tumors from embryonic versus postnatal cerebellar NSCs demonstrating Sonic Hedgehog (SHH) dependence and SHH independence, respectively. These differences were regulated in part by the transcription factor SOX9, activated in the SHH subclass of human medulloblastoma. Our results demonstrate context-dependent transformation of NSCs in response to a common oncogenic signal. [Display omitted] ► N-MYC contributes to both glioma and medulloblastoma ► N-MYC drives either SHH-dependent or -independent tumors, based on NSC age ► NSCs from different brain regions generate tumors with distinct signaling programs ► Transcription factor SOX9 is activated in SHH-dependent brain tumor cells