No abstract

Although fibrotic stroma forms an integral component of pancreatic diseases, whether fibroblasts programmed by different types of pancreatic diseases are phenotypically distinct remains unknown.Here we show that fibroblasts isolated from patients with pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP), periampullary tumors (PAT), and adjacent normal (NA) tissue (N=34) have distinct mRNA and miRNA profiles. Compared to NA-fibroblasts, PDAC-associated fibroblasts were generally less sensitive to an anti-fibrotic stimulus (NPPB) and more responsive to positive regulators of activation such as TGFβ1 and WNT. Of the disease-associated fibroblasts examined, PDAC-and CP-derived fibroblasts shared greatest similarity, yet PDAC-associated fibroblasts expressed higher levels of Tenascin C (TNC), a finding attributable to miR-137, a novel regulator of TNC. TNC protein and transcript levels were higher in PDAC tissue versus CP tissue and were associated with greater levels of stromal activation, and conditioned media from TNC-depleted PDAC-associated fibroblasts modestly increased both PDAC cell proliferation and PDAC cell migration, indicating that stromal TNC may have inhibitory effects on PDAC cells. Finally, circulating TNC levels were higher in patients with PDAC compared to CP. Our characterization of pancreatic fibroblast programming as disease-specific has consequences for therapeutic targeting and for the manner in which fibroblasts are used in research.

We have generated pancreatic-cancer derived cell lines in which gene expression is fully controllable.