Genetic ablation of Smoothened in pancreatic fibroblasts increases acinar–ductal metaplasia

  1. Michael C. Ostrowski1,2
  1. 1Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA;
  2. 2Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
  3. 3Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907, USA;
  4. 4the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA;
  5. 5the Bindley Bioscience Center, Purdue University, West Lafayette, Indiana 47907, USA;
  6. 6Department of Biomedical Informatics' Center for Biostatistics, The Ohio State University, Columbus, Ohio 43210, USA
  7. 7Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, USA
  8. 8Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA
  1. Corresponding authors: michael.ostrowski{at}osumc.edu, jinghai.wu{at}osumc.edu
  1. 9 These authors contributed equally to this work.

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 KrasG12D 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 KrasG12D/Tp53R172H pancreatic tumor cells in vivo and in vitro. These results define a non-cell-autonomous mechanism modulating KrasG12D-driven ADM that is balanced by cross-talk between Hedgehog/SMO and AKT/GLI2 pathways in stromal fibroblasts.

Keywords

Footnotes

  • Received April 28, 2016.
  • Accepted August 8, 2016.

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