Background : Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies, with median survival of less than one year and overall 5-year overall survival rate of less than 5%. However, specific regulator of PDAC has yet to be established. In the present study, we investigated whether Neural Wiskott-Aldrich Syndrome Protein (N-WASP) plays a role in distant metastasis of PDAC.

Methods : Between June 2002 and December 2012, 81 patients underwent radical curative resection for pancreatic cancer at Gangnam Severance Hospital. Pancreatic cancer cell lines MIA PaCa-2, PANC-1 were used for in vitro and in vivo study. To evaluate the endogenous expression level of N-WASP, we purified the whole RNA and protein to perform the qPCR, RT-PCR and Western blot. And we confirmed the motility and invasiveness of MIA PaCa-2 and PANC-1. By using of pancreatic cancer cell lines, orthotopic mouse model of pancreatic cancer was established.

Results : We found that N-WASP was markedly expressed in PDAC patients. Knockdown of N-WASP in pancreatic cancer cell significantly decreased cell invasion and migration. Using gene expression profile studies, we found that N-WASP is a novel mediator of epithelial?mesenchymal transition (EMT). Knockdown of N-WASP expression with siRNA inhibited cell migration and EMT. We also observed that the lysyl oxidase-like 2 (LOXL2) and focal adhesion kinase (FAK) is associated with the N-WASP-mediated response, thereby modulating EMT and invadopodia. Finally, N-WASP depletion significantly reduced the incidence of liver and lung metastatic lesions in orthotopic mouse models of pancreatic cancer.

Conclusions : These results identify a new role for N-WASP signaling in EMT and invadopodia that regulate their intercellular communication with tumor cells to inhibits pancreatic cancer metastasis.