title: Stromal response to Hedgehog signaling restrains pancreatic cancer progression.
abstract: Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA progression by expression of Hh ligands in the neoplastic epithelium and paracrine response in the stromal fibroblasts. Clinical trials to test this possibility, however, have yielded disappointing results. To further investigate the role of Hh signaling in the formation of PDA and its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), we examined the effects of genetic or pharmacologic inhibition of Hh pathway activity in three distinct genetically engineered mouse models and found that Hh pathway inhibition accelerates rather than delays progression of oncogenic Kras-driven disease. Notably, pharmacologic inhibition of Hh pathway activity affected the balance between epithelial and stromal elements, suppressing stromal desmoplasia but also causing accelerated growth of the PanIN epithelium. In striking contrast, pathway activation using a small molecule agonist caused stromal hyperplasia and reduced epithelial proliferation. These results indicate that stromal response to Hh signaling is protective against PDA and that pharmacologic activation of pathway response can slow tumorigenesis. Our results provide evidence for a restraining role of stroma in PDA progression, suggesting an explanation for the failure of Hh inhibitors in clinical trials and pointing to the possibility of a novel type of therapeutic intervention.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine,Division of Oncology, Department of Medicine.
authors.forename: John J
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Rushika M
authors.initials: RM
authors.lastname: Perera
authors.affiliation: Molecular Imaging Program, Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Huaijun
authors.initials: H
authors.lastname: Wang
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine.
authors.forename: Dai-Chen
authors.initials: DC
authors.lastname: Wu
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine.
authors.forename: X Shawn
authors.initials: XS
authors.lastname: Liu
authors.affiliation: Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; and.
authors.forename: Shiwei
authors.initials: S
authors.lastname: Han
authors.affiliation: Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Julien
authors.initials: J
authors.lastname: Fitamant
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine.
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Jones
authors.affiliation: Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Krishna S
authors.initials: KS
authors.lastname: Ghanta
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine.
authors.forename: Sally
authors.initials: S
authors.lastname: Kawano
authors.affiliation: Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Julia M
authors.initials: JM
authors.lastname: Nagle
authors.affiliation: Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.affiliation: Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; and.
authors.forename: Yves
authors.initials: Y
authors.lastname: Boucher
authors.affiliation: Department of Chemical and Systems Biology, and.
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Chemical and Systems Biology, and.
authors.forename: James K
authors.initials: JK
authors.lastname: Chen
authors.affiliation: Molecular Imaging Program, Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Jürgen K
authors.initials: JK
authors.lastname: Willmann
authors.affiliation: Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; pbeachy@stanford.edu Bardeesy.Nabeel@mgh.harvard.edu.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine,Department of Biochemistry,Howard Hughes Medical Institute, Stanford, CA 94305 pbeachy@stanford.edu Bardeesy.Nabeel@mgh.harvard.edu.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beachy
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Sonic hedgehog; cancer therapy; cerulein; hedgehog agonist; tumor stroma