Nardilysin inhibits pancreatitis and suppresses pancreatic ductal adenocarcinoma initiation in mice.

Abstract

Nardilysin (NRDC), a zinc peptidase, exhibits multiple localisation-dependent functions including as an enhancer of ectodomain shedding in the extracellular space and a transcriptional coregulator in the nucleus. In this study, we investigated its functional role in exocrine pancreatic development, homeostasis and the formation of pancreatic ductal adenocarcinoma (PDA). We analysed <i>Ptf1a-Cre; Nrdc^flox/flox</i> mice to investigate the impact of <i>Nrdc</i> deletion. Pancreatic acinar cells were isolated from <i>Nrdc^flox/flox</i> mice and infected with adenovirus expressing Cre recombinase to examine the impact of <i>Nrdc</i> inactivation. Global gene expression in <i>Nrdc-cKO</i> pancreas was analysed compared with wild-type pancreas by microarray analysis. We also analysed <i>Ptf1a-Cre; Kras^G12D; Nrdc^flox/flox</i> mice to investigate the impact of <i>Nrdc</i> deletion in the context of oncogenic Kras. A total of 51 human samples of pancreatic intraepithelial lesions (PanIN) and PDA were examined by immunohistochemistry for NRDC. We found that pancreatic deletion of <i>Nrdc</i> leads to spontaneous chronic pancreatitis concomitant with acinar-to-ductal conversion, increased apoptosis and atrophic pancreas in mice. Acinar-to-ductal conversion was observed mainly through a non-cell autonomous mechanism, and the expression of several chemokines was significantly increased in <i>Nrdc</i>-null pancreatic acinar cells. Furthermore, pancreatic deletion of <i>Nrdc</i> dramatically accelerated <i>Kras^G12D</i> -driven PanIN and subsequent PDA formation in mice. These data demonstrate a previously unappreciated anti-inflammatory and tumour suppressive functions of Nrdc in the pancreas in mice. Finally, absence of NRDC expression was observed in a subset of human PanIN and PDA. Nrdc inhibits pancreatitis and suppresses PDA initiation in mice.