Journal
CANCER CELL
Volume 21, Issue 5, Pages 601-613Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2012.04.012
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Funding
- Pediatric Brain Tumor Foundation
- Swedish Research Council
- Swedish Cancer Society
- Swedish Childhood Cancer Foundation
- Ake Wibergs Stiftelse
- Lions Cancerforskningsfond
- Stiftelsen Lars Hiertas Minne
- Children's Brain Tumor Foundation
- NIH [R01 CA133091, CA148699, CA159859, K08 NS063456]
- Hellmann Fellowship Award
- American Brain Tumor Association
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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-myc(T58A) into neural stem cells (NSCs) from perinatal murine cerebellum, brain stem, and forebrain. Transplantation of N-myc(WT) NSCs was insufficient for tumor formation. N-myc(T58A) 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.
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