Neural Wiskott-Aldrich syndrome protein(N-WASP)promotes distant metastasis in pancreatic ductal adenocarcinoma via activation of LOXL2

Pancreatic ductal adenocarcinoma(PDAC)is one of the most aggressive solid malignancies.A specific mechanism of its metastasis has not been established.In this study,we investigated whether Neural Wiskott-Aldrich syndrome protein(N-WASP)plays a role in distant metastasis of PDAC.We found that N-WASP is markedly expressed in clinical patients with PDAC.Clinical analysis showed a notably more distant metastatic pattern in the N-WASP-high group compared to the N-WASP-low group.N-WASP was noted to be a novel mediator of epithelialmesenchymal transition(EMT)via gene expression profile studies.Knockdown of N-WASP in pancreatic cancer cells significantly inhibited cell invasion,migration,and EMT.We also observed positive association of lysyl oxidase-like 2(LOXL2)and focal adhesion kinase(FAK)with the N-WASP-mediated response,wherein EMT and invadopodia function were modulated.Both N-WASP and LOXL2 depletion significantly reduced the incidence of liver and lung metastatic lesions in orthotopic mouse models of pancreatic cancer.These results elucidate a novel role for N-WASP signaling associated with LOXL2 in EMT and invadopodia function,with respect to regulation of intercellular communication in tumor cells for promoting pancreatic cancer metastasis.These findings may aid in the development of therapeutic strategies against pancreatic cancer.

Clinical validation of scoring systems of postoperative pancreatic fistula after pancreatoduodenectomy: applicability to Eastern cohorts?

Background:Although several prediction models for the occurrence of postoperative pancreatic fistula(POPF)after pancreatoduodenectomy(PD)exist,all were established using Western cohorts.Large-scale external validation studies in Eastern cohorts that consider demographic variables including lower body mass index(BMI)are scarce.The purpose of this study was to externally validate POPF prediction models using nationwide large-scale Korean cohorts.Methods:Nine tertiary university hospitals in the Republic of Korea participated.Patients'preoperative characteristics,intraoperative factors,and pathologic findings were evaluated.POPF grades were determined according to the 2016 International Study Group on Pancreatic Surgery definition.Three POPF risk models(Callery,Roberts,and Mungroop)were selected for external validation.Results:A total of 1,898 PD patients were enrolled.A non-pancreatic disease diagnosis[hazard ratio(HR),1.856;95%confidence interval(CI),1.223–2.817;P=0.004),higher preoperative BMI(HR,1.069;95%CI,1.019–1.121;P=0.006),and soft pancreatic texture(HR,1.859;95%CI,1.264–2.735;P=0.002)were independent risk factors for clinically relevant POPF(CR-POPF).The area under the receiver operating characteristic curve(AUC)values were 0.61,0.64,and 0.63 on the Callery,Roberts,and Mungroop models,respectively;all were lower than those published in each external validation study.Conclusions:Western POPF prediction models performed less well when applied to Korean cohorts.Thus,a large-scale Eastern-specific and externally validated POPF prediction model is needed.