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

176 Citations (Scopus)

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

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Hedgehogs
Neoplasms
Gene Components
Surveys and Questionnaires
Medulloblastoma
Rhabdomyosarcoma
Penetrance
Basal Cell Carcinoma
Platelet-Derived Growth Factor
Somatomedins
Tamoxifen
Transgenes
Oncogenes
Transcriptome
Prostate
Carcinogenesis
Theoretical Models
Up-Regulation
Epithelium
Alleles

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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

A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway. / Mao, Junhao; Ligon, Keith L.; Rakhlin, Elena Y.; Thayer, Sarah P; Bronson, Roderick T.; Rowitch, David; McMahon, Andrew P.

In: Cancer Research, Vol. 66, No. 20, 15.10.2006, p. 10171-10178.

Research output: Contribution to journalArticle

Mao, J, Ligon, KL, Rakhlin, EY, Thayer, SP, Bronson, RT, Rowitch, D & McMahon, AP 2006, 'A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway', Cancer Research, vol. 66, no. 20, pp. 10171-10178. https://doi.org/10.1158/0008-5472.CAN-06-0657
Mao, Junhao ; Ligon, Keith L. ; Rakhlin, Elena Y. ; Thayer, Sarah P ; Bronson, Roderick T. ; Rowitch, David ; McMahon, Andrew P. / A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway. In: Cancer Research. 2006 ; Vol. 66, No. 20. pp. 10171-10178.
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