Author:
Swartling Fredrik J.,Grimmer Matthew R.,Hackett Christopher S.,Northcott Paul A.,Fan Qi-Wen,Goldenberg David D.,Lau Jasmine,Masic Selma,Nguyen Kim,Yakovenko Slava,Zhe Xiao-Ning,Flynn Gilmer Heather C.,Collins Rodney,Nagaoka Mai,Phillips Joanna J.,Jenkins Robert B.,Tihan Tarik,Vandenberg Scott R.,James C. David,Tanaka Kohichi,Taylor Michael D.,Weiss William A.,Chesler Louis
Abstract
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 ∼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.
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
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