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Genetic ablation of Smoothened in pancreatic fibroblasts increases acinar-ductal metaplasia.
Liu, Xin; Pitarresi, Jason R; Cuitiño, Maria C; Kladney, Raleigh D; Woelke, Sarah A; Sizemore, Gina M; Nayak, Sunayana G; Egriboz, Onur; Schweickert, Patrick G; Yu, Lianbo; Trela, Stefan; Schilling, Daniel J; Halloran, Shannon K; Li, Maokun; Dutta, Shourik; Fernandez, Soledad A; Rosol, Thomas J; Lesinski, Gregory B; Shakya, Reena; Ludwig, Thomas; Konieczny, Stephen F; Leone, Gustavo; Wu, Jinghai; Ostrowski, Michael C.
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  • Liu X; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
  • Pitarresi JR; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
  • Cuitiño MC; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
  • Kladney RD; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
  • Woelke SA; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA;
  • Sizemore GM; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
  • Nayak SG; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
  • Egriboz O; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
  • Schweickert PG; 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;
  • Yu L; Department of Biomedical Informatics' Center for Biostatistics, The Ohio State University, Columbus, Ohio 43210, USA.
  • Trela S; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
  • Schilling DJ; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
  • Halloran SK; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
  • Li M; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
  • Dutta S; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
  • Fernandez SA; Department of Biomedical Informatics' Center for Biostatistics, The Ohio State University, Columbus, Ohio 43210, USA.
  • Rosol TJ; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, USA.
  • Lesinski GB; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
  • Shakya R; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA;
  • Ludwig T; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
  • Konieczny SF; 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;
  • Leone G; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
  • Wu J; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
  • Ostrowski MC; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
Genes Dev ; 30(17): 1943-55, 2016 09 01.
Article en En | MEDLINE | ID: mdl-27633013
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Carcinoma Ductal Pancreático / Receptor Smoothened / Metaplasia Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Genes Dev Asunto de la revista: BIOLOGIA MOLECULAR Año: 2016 Tipo del documento: Article
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Carcinoma Ductal Pancreático / Receptor Smoothened / Metaplasia Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Genes Dev Asunto de la revista: BIOLOGIA MOLECULAR Año: 2016 Tipo del documento: Article