title: Genetic ablation of Smoothened in pancreatic fibroblasts increases acinar-ductal metaplasia.
abstract: The contribution of the microenvironment to pancreatic acinar-to-ductal metaplasia (ADM), a preneoplastic transition in oncogenic Kras-driven pancreatic cancer progression, is currently unclear. Here we show that disruption of paracrine Hedgehog signaling via genetic ablation of Smoothened (Smo) in stromal fibroblasts in a Kras(G12D) mouse model increased ADM. Smo-deleted fibroblasts had higher expression of transforming growth factor-α (Tgfa) mRNA and secreted higher levels of TGFα, leading to activation of EGFR signaling in acinar cells and increased ADM. The mechanism involved activation of AKT and noncanonical activation of the GLI family transcription factor GLI2. GLI2 was phosphorylated at Ser230 in an AKT-dependent fashion and directly regulated Tgfa expression in fibroblasts lacking Smo Additionally, Smo-deleted fibroblasts stimulated the growth of Kras(G12D)/Tp53(R172H) pancreatic tumor cells in vivo and in vitro. These results define a non-cell-autonomous mechanism modulating Kras(G12D)-driven ADM that is balanced by cross-talk between Hedgehog/SMO and AKT/GLI2 pathways in stromal fibroblasts.
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
authors.forename: Jason R
authors.initials: JR
authors.lastname: Pitarresi
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
authors.forename: Maria C
authors.initials: MC
authors.lastname: Cuitiño
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
authors.forename: Raleigh D
authors.initials: RD
authors.lastname: Kladney
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA;
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Woelke
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
authors.forename: Gina M
authors.initials: GM
authors.lastname: Sizemore
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
authors.forename: Sunayana G
authors.initials: SG
authors.lastname: Nayak
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
authors.forename: Onur
authors.initials: O
authors.lastname: Egriboz
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907, USA; the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA; the Bindley Bioscience Center, Purdue University, West Lafayette, Indiana 47907, USA;
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Schweickert
authors.affiliation: Department of Biomedical Informatics' Center for Biostatistics, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Lianbo
authors.initials: L
authors.lastname: Yu
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
authors.forename: Stefan
authors.initials: S
authors.lastname: Trela
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schilling
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
authors.forename: Shannon K
authors.initials: SK
authors.lastname: Halloran
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
authors.forename: Maokun
authors.initials: M
authors.lastname: Li
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
authors.forename: Shourik
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Department of Biomedical Informatics' Center for Biostatistics, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Soledad A
authors.initials: SA
authors.lastname: Fernandez
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rosol
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Lesinski
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA;
authors.forename: Reena
authors.initials: R
authors.lastname: Shakya
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907, USA; the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA; the Bindley Bioscience Center, Purdue University, West Lafayette, Indiana 47907, USA;
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Konieczny
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
authors.forename: Gustavo
authors.initials: G
authors.lastname: Leone
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
authors.forename: Jinghai
authors.initials: J
authors.lastname: Wu
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
authors.forename: Michael C
authors.initials: MC
authors.lastname: Ostrowski
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000473:pathology; D017353:Gene Deletion; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008679:Metaplasia / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D015398:Signal Transduction / Q000235:genetics; D000072086:Smoothened Receptor / Q000235:genetics* / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000075746:Zinc Finger Protein Gli2
chemical_list: C000618551:Gli2 protein, mouse; D051741:Kruppel-Like Transcription Factors; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D016211:Transforming Growth Factor alpha; D000075746:Zinc Finger Protein Gli2; C541485:EGFR protein, mouse; D066246:ErbB Receptors
keywords: AKT signaling; EGFR signaling; acinar-to-ductal metaplasia; hedgehog signaling; stromal fibroblast