Poster abstracts
Poster number 36 submitted by Xin Liu
Genetic Ablation of Smoothened in Pancreatic Fibroblasts Augments Acinar-Ductal Metaplasia Induced by Oncogenic Kras
Xin Liu (Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA), Jason R. Pitarresi (Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA), Jinghai Wu (Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA)
Abstract:
The contribution of the microenvironment to pancreatic acinar-to-ductal (ADM) is currently unclear. Here we show that disruption of paracrine hedgehog signaling via genetic ablation of Smoothened (Smo) in stromal fibroblasts in a KrasG12D genetically engineered mouse model accelerated ADM formation. ADM was induced by activation of epithelial growth factor receptor (EGFR) through increased transforming growth factor alpha (TGF-) production in SMO-deleted fibroblasts. Increased expression and activity of the GLI family zinc finger protein 2 (GLI) transcription factor was the primary means of enhanced TGF- in fibroblasts. Upstream of TGF-, SMO-depleted fibroblasts exhibited activated p-AKT, which led to direct phosphorylation and stabilization of GLI2. These results define a non-cell autonomous mechanism that increased KrasG12D-driven ADM when hedgehog signaling is disrupted in stromal fibroblasts.
Keywords: pancreatic cancer , Hedgehog signaling