A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway

Junhao Mao, Keith L. Ligon, Elena Y. Rakhlin, Sarah P. Thayer, Roderick T. Bronson, David Rowitch, Andrew P. McMahon

Research output: Contribution to journalArticle

188 Scopus citations

Abstract

We report a novel mouse model for the generation of sporadic tumors and show the efficiency of this approach by surveying Hedgehog (Hh)-related tumors. Up-regulation of the Hh pathway is achieved by conditionally regulated expression of an activated allele of Smoothened (R26-SmoM2) using either sporadic leakage or global postnatal induction of a ubiquitously expressed inducible Cre transgene (CAGGS-CreER). Following postnatal tamoxifen induction, CAGGS-CreER; R26-SmoM2 mice developed tumors with short latency and high penetrance. All mice exhibited rhabdomyosarcoma and basal cell carcinoma; 40% also developed medulloblastoma. In addition, mice showed a novel pancreatic lesion resembling low-grade mucinous cystic neoplasms in humans. In contrast, widespread activation of SmoM2 in the postnatal prostate epithelium results in no detectable morphologic outcome in 12-month-old mice. Comparison of gene expression profiles among diverse tumors identified several signature genes, including components of platelet-derived growth factor and insulin-like growth factor pathways, which may provide a common mechanistic link to the Hh-related malignancies. This experimental model provides a robust tool for exploring the process of Hh-dependent tumorigenesis and the treatment of such tumors. More generally, this approach provides a genetic platform for identifying tumorigenic potential in putative oncogenes and tumor suppressors and for more effective modeling of sporadic cancers in mice.

Original languageEnglish (US)
Pages (from-to)10171-10178
Number of pages8
JournalCancer Research
Volume66
Issue number20
DOIs
StatePublished - Oct 15 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Mao, J., Ligon, K. L., Rakhlin, E. Y., Thayer, S. P., Bronson, R. T., Rowitch, D., & McMahon, A. P. (2006). A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway. Cancer Research, 66(20), 10171-10178. https://doi.org/10.1158/0008-5472.CAN-06-0657