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 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 01, 2016
- Source ID
- 10.1101/gad.283499.116
Entities
People
- Daniel J. Schilling
- Gina M. Sizemore
- Gregory B. Lesinski
- Gustavo Leone
- Jason R Pitarresi
- Jinghai Wu
- Lianbo Yu
- Maokun Li
- Maria C. Cuitiño
- Michael C. Ostrowski
- Onur Egriboz
- Patrick G. Schweickert
- Raleigh D. Kladney
- Reena Shakya
- Sarah A. Woelke
- Shannon K. Halloran
- Shourik Dutta
- Soledad A. Fernandez
- Stefan Trela
- Stephen F. Konieczny
- Sunayana G. Nayak
- Thomas J. Rosol
- Thomas Ludwig
- Xin Liu
Organizations
- National Institutes of Health
- United States Department of Defense