title: Canonical wnt signaling is required for pancreatic carcinogenesis.
abstract: Wnt ligand expression and activation of the Wnt/β-catenin pathway have been associated with pancreatic ductal adenocarcinoma, but whether Wnt activity is required for the development of pancreatic cancer has remained unclear. Here, we report the results of three different approaches to inhibit the Wnt/β-catenin pathway in a established transgenic mouse model of pancreatic cancer. First, we found that β-catenin null cells were incapable of undergoing acinar to ductal metaplasia, a process associated with development of premalignant pancreatic intraepithelial neoplasia lesions. Second, we addressed the specific role of ligand-mediated Wnt signaling through inducible expression of Dkk1, an endogenous secreted inhibitor of the canonical Wnt pathway. Finally, we targeted the Wnt pathway with OMP-18R5, a therapeutic antibody that interacts with multiple Frizzled receptors. Together, these approaches showed that ligand-mediated activation of the Wnt/β-catenin pathway is required to initiate pancreatic cancer. Moreover, they establish that Wnt signaling is also critical for progression of pancreatic cancer, a finding with potential therapeutic implications.
authors.affiliation: Department of Surgery, University of Michigan Medical School, 1500 E Medical Center Drive, Ann Arbor, MI 48109, USA.
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: John P
authors.initials: JP
authors.lastname: Morris
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.forename: Heather K
authors.initials: HK
authors.lastname: Schofield
authors.forename: Austin
authors.initials: A
authors.lastname: Gurney
authors.forename: Diane M
authors.initials: DM
authors.lastname: Simeone
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Millar
authors.forename: Timothy
authors.initials: T
authors.lastname: Hoey
authors.forename: Matthias
authors.initials: M
authors.lastname: Hebrok
authors.forename: Marina
authors.initials: M
authors.lastname: Pasca di Magliano
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051176:beta Catenin