GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation

  1. Olivier Nolan-Stevaux1,2,
  2. Janet Lau2,3,
  3. Morgan L. Truitt1,2,
  4. Gerald C. Chu4,
  5. Matthias Hebrok2,3,
  6. Martin E. Fernández-Zapico5 and
  7. Douglas Hanahan1,2,6,7
  1. 1Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94143, USA;
  2. 2Diabetes Center, University of California at San Francisco, San Francisco, California 94143, USA;
  3. 3Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA;
  4. 4Department of Medical Oncology, Dana Farber Cancer Center, Boston Massachusetts 02143, USA;
  5. 5Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA;
  6. 6Department of Biophysics and Biochemistry, University of California at San Francisco, San Francisco, California 94143, USA

    Abstract

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by the deregulation of the hedgehog signaling pathway. The Sonic Hedgehog ligand (Shh), absent in the normal pancreas, is highly expressed in pancreatic tumors and is sufficient to induce neoplastic precursor lesions in mouse models. We investigated the mechanism of Shh signaling in PDAC carcinogenesis by genetically ablating the canonical bottleneck of hedgehog signaling, the transmembrane protein Smoothened (Smo), in the pancreatic epithelium of PDAC-susceptible mice. We report that multistage development of PDAC tumors is not affected by the deletion of Smo in the pancreas, demonstrating that autocrine Shh–Ptch–Smo signaling is not required in pancreatic ductal cells for PDAC progression. However, the expression of Gli target genes is maintained in Smo-negative ducts, implicating alternative means of regulating Gli transcription in the neoplastic ductal epithelium. In PDAC tumor cells, we find that Gli transcription is decoupled from upstream Shh–Ptch–Smo signaling and is regulated by TGF-β and KRAS, and we show that Gli1 is required both for survival and for the KRAS-mediated transformed phenotype of cultured PDAC cancer cells.

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    1. doi: 10.1101/gad.1753809 Genes & Dev. 23: 24-36 Copyright © 2009 by Cold Spring Harbor Laboratory Press

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