Pleiotropic role for MYCN in medulloblastoma.
Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Sonic Hedgehog (SHH) signaling drives a minority of MB, correlating with desmoplastic pathology and favorable outcome. The majority, however, arises independently of SHH and displays classic or large cell anaplastic (LCA) pathology and poor prognosis. To identify common signaling abnormalities, we profiled mRNA, demonstrating misexpression of MYCN in the majority of human MB and negligible expression in normal cerebella. We clarified a role in pathogenesis by targeting MYCN (and luciferase) to cerebella of transgenic mice. MYCN-driven MB showed either classic or LCA pathologies, with Shh signaling activated in approximately 5% of tumors, demonstrating that MYCN can drive MB independently of Shh. MB arose at high penetrance, consistent with a role for MYCN in initiation. Tumor burden correlated with bioluminescence, with rare metastatic spread to the leptomeninges, suggesting roles for MYCN in both progression and metastasis. Transient pharmacological down-regulation of MYCN led to both clearance and senescence of tumor cells, and improved survival. Targeted expression of MYCN thus contributes to initiation, progression, and maintenance of MB, suggesting a central role for MYCN in pathogenesis.
Swartling
Fredrik J
FJ
University of California at San Francisco, San Francisco, California 94158, USA.
Grimmer
Matthew R
MR
Hackett
Christopher S
CS
Northcott
Paul A
PA
Fan
Qi-Wen
QW
Goldenberg
David D
DD
Lau
Jasmine
J
Masic
Selma
S
Nguyen
Kim
K
Yakovenko
Slava
S
Zhe
Xiao-Ning
XN
Gilmer
Heather C Flynn
HC
Collins
Rodney
R
Nagaoka
Mai
M
Phillips
Joanna J
JJ
Jenkins
Robert B
RB
Tihan
Tarik
T
Vandenberg
Scott R
SR
James
C David
CD
Tanaka
Kohichi
K
Taylor
Michael D
MD
Weiss
William A
WA
Chesler
Louis
L
D027322:Amino Acid Transport System X-AG / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology; D002531:Cerebellum / Q000378:metabolism; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008527:Medulloblastoma / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D000071447:N-Myc Proto-Oncogene Protein; D009362:Neoplasm Metastasis / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*
D027322:Amino Acid Transport System X-AG; D053823:Hedgehog Proteins; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins