Genetic Ablation of Smoothened in Tumor-Associated Fibroblasts Promotes Pancreatic Tumorigenesis

Biological Sciences: 2nd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)Pancreatic cancer remains an overwhelmingly fatal disease with less than 5% of patients surviving beyond 5 years, largely due to our lack of understanding of the complexity of the disease. Many recent reports have begun to highlight the potential role that stromal cells—fibroblasts in particular—may have on pancreatic tumor cell biology and this report provides data that supports the theory of tumor-stroma co-evolution in pancreatic cancer. Here we use a novel mouse model to show that Smoothened (Smo) in the tumor-associated stroma suppresses pancreatic tumor initiation and development. We observed an increase in tumorigenesis events such as acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions when Smo is conditionally deleted in pancreatic cancer associated fibroblasts (CAFs). To determine how Smo in fibroblasts is able to effect tumor progression, we harvested pancreatic CAFs from Smo-deleted and Smo-intact tumor bearing mice and performed microarray gene expression analysis. We found that Smo deleted CAFs had significantly altered the tumor suppressor PTEN, resulting in misregulated Phosphoinositide 3-kinase (PI3K) oncogenic pathway signaling. Thus, Smo ablation in pancreatic fibroblasts enhanced pancreatic tumor initiation primarily through loss of PTEN in fibroblasts. This report shows that deleting a gene in pancreatic fibroblasts causes a change in tumor-stroma co-evolution and that Smo is able to act as a novel tumor suppressor in cancer associated fibroblasts to promote pancreatic carcinogenesis.A five-year embargo was granted for this item