Pleiotropic role for MYCN in medulloblastoma (original) (raw)

  1. Matthew R. Grimmer1,6,
  2. Christopher S. Hackett1,
  3. Paul A. Northcott2,
  4. Qi-Wen Fan1,
  5. David D. Goldenberg1,
  6. Jasmine Lau1,
  7. Selma Masic1,
  8. Kim Nguyen1,
  9. Slava Yakovenko1,
  10. Xiao-Ning Zhe1,
  11. Heather C. Flynn Gilmer3,
  12. Rodney Collins1,
  13. Mai Nagaoka4,
  14. Joanna J. Phillips1,
  15. Robert B. Jenkins3,
  16. Tarik Tihan1,
  17. Scott R. Vandenberg1,
  18. C. David James1,
  19. Kohichi Tanaka4,
  20. Michael D. Taylor2,
  21. William A. Weiss1,7 and
  22. Louis Chesler5,8
  23. 1University of California at San Francisco, San Francisco, California 94158, USA;
  24. 2The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada;
  25. 3Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA;
  26. 4Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan;
  27. 5The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom
  28. ↵6 These authors contributed equally to this work.

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.

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