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Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis

Author

Listed:
  • Sarah P. Thayer

    (Massachusetts General Hospital and Harvard Medical School)

  • Marina Pasca di Magliano

    (University of California)

  • Patrick W. Heiser

    (University of California)

  • Corinne M. Nielsen

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Drucilla J. Roberts

    (Massachusetts General Hospital and Harvard Medical School)

  • Gregory Y. Lauwers

    (Massachusetts General Hospital and Harvard Medical School)

  • Yan Ping Qi

    (University of California)

  • Stephan Gysin

    (University of California)

  • Carlos Fernández-del Castillo

    (Massachusetts General Hospital and Harvard Medical School)

  • Vijay Yajnik

    (Massachusetts General Hospital and Harvard Medical School)

  • Bozena Antoniu

    (Massachusetts General Hospital and Harvard Medical School)

  • Martin McMahon

    (University of California)

  • Andrew L. Warshaw

    (Massachusetts General Hospital and Harvard Medical School)

  • Matthias Hebrok

    (University of California)

Abstract

Hedgehog signalling—an essential pathway during embryonic pancreatic development, the misregulation of which has been implicated in several forms of cancer—may also be an important mediator in human pancreatic carcinoma1,2,3,4,5,6,7,8. Here we report that sonic hedgehog, a secreted hedgehog ligand, is abnormally expressed in pancreatic adenocarcinoma and its precursor lesions: pancreatic intraepithelial neoplasia (PanIN). Pancreata of Pdx–Shh mice (in which Shh is misexpressed in the pancreatic endoderm) develop abnormal tubular structures, a phenocopy of human PanIN-1 and -2. Moreover, these PanIN-like lesions also contain mutations in K-ras and overexpress HER-2/neu, which are genetic mutations found early in the progression of human pancreatic cancer. Furthermore, hedgehog signalling remains active in cell lines established from primary and metastatic pancreatic adenocarcinomas. Notably, inhibition of hedgehog signalling by cyclopamine induced apoptosis and blocked proliferation in a subset of the pancreatic cancer cell lines both in vitro and in vivo. These data suggest that this pathway may have an early and critical role in the genesis of this cancer, and that maintenance of hedgehog signalling is important for aberrant proliferation and tumorigenesis.

Suggested Citation

  • Sarah P. Thayer & Marina Pasca di Magliano & Patrick W. Heiser & Corinne M. Nielsen & Drucilla J. Roberts & Gregory Y. Lauwers & Yan Ping Qi & Stephan Gysin & Carlos Fernández-del Castillo & Vijay Yaj, 2003. "Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis," Nature, Nature, vol. 425(6960), pages 851-856, October.
    • Handle: RePEc:nat:nature:v:425:y:2003:i:6960:d:10.1038_nature02009
    DOI: 10.1038/nature02009
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    Cited by:

    1. Sebastien Martinez & Shifei Wu & Michael Geuenich & Ahmad Malik & Ramona Weber & Tristan Woo & Amy Zhang & Gun Ho Jang & Dzana Dervovic & Khalid N. Al-Zahrani & Ricky Tsai & Nassima Fodil & Philippe G, 2024. "In vivo CRISPR screens reveal SCAF1 and USP15 as drivers of pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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