GFP-fascin−rescued cells generated protrusions that more effectively transmigrated than fascin nulls ( Figure 7C and Video 6). Nude mice injected with fascin-deficient PDAC cells developed significantly fewer mesenteric or diaphragm metastatic foci than those with fascin-rescued cells ( Figure 7E and F). These results are consistent with our spontaneous mouse model and suggest that targeting the interaction of PDAC cells with the mesothelium through fascin depletion is sufficient
to reduce metastasis in vivo. Nearly all human PDAC expressed fascin, and a higher fascin histoscore correlated with poor outcomes, vascular invasion, and time to recurrence. Similar correlations have been reported Everolimus in vitro for hepatocellular and extrahepatic bile duct carcinomas.29 and 30 Fascin expression in smaller cohorts of human PDAC and PanIN,31 and 32 and also in pancreatobiliary adenocarcinomas33 and pancreatic intraductal papillary mucinous carcinoma,34 correlated RO4929097 price with shorter survival times and more advanced stages. Fascin expression contributes to progression of human PDAC, but is only of borderline significance as a prognostic indicator, indicating that other factors contribute to recurrence and spread. Fascin is a wnt target in colorectal
cancer, where it localizes to tumor invasive fronts but is down-regulated in metastases.35 However, in KrasG12D- and p53R172H-driven pancreatic cancer, fascin is evenly expressed in tumors and remains highly expressed in liver and peritoneal metastases. Unlike colorectal cancer, the role of wnt signaling in pancreatic cancer progression is less clear,36 and we find that fascin is an EMT target of the Tf slug. Slug is expressed in pancreatic endocrine progenitor cells and
effects EMT changes and migration during early embryonic development.6 We speculate that PDAC cells might reacquire slug and fascin during a partial reversion to an embryonic migratory state. There is controversy about whether gene changes that confer metastatic dissemination find more of pancreatic cancer (or other cancers) occur early in tumor formation or later. A recent study provided compelling evidence based on lineage tracing of cells by tumor mutation analysis that metastasis could occur even before there was a recognizable tumor.10 Our finding that fascin expression happens during late PanIN to PDAC transition suggest that EMT changes that promote metastasis start to happen early. EMT has been correlated with tumor-initiating (stem) cell properties and as a part of an EMT program.37 Fascin expression might allow tumor stem cells to thrive during initial tumor formation, as well as later during metastasis. Perhaps primary tumors and metastases first arise from small nests of fascin-positive cells in PanIN3. In this case, expression of fascin in PanINs might be predictive of tumor formation and metastasis. Fascin is not only expressed in PDAC tumor cells, but also in stroma of PDAC and of some PanIN.