PAK4 orchestrates dual transcriptional and post-translational repression of E-cadherin to promote epithelial-to-mesenchymal transition and invasiveness in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor prognosis and a high propensity for metastasis. Analysis of TCGA data revealed that PAK4 overexpression was associated with inferior survival outcomes in PDAC patients. In this preclinical study, PAK4-amplified PDAC cells significantly enhanced migratory capacity compared to wild-type cells. Knockdown of PAK4 in these cells suppressed migration by increasing and stabilizing E-cadherin, accompanied by decreased Cdc42 activity. Conversely, constitutive expression of Flag-PAK4 in wild-type cells reduced E-cadherin levels while promoting cell migration, invasion, and motility through elevated Cdc42 activity. Immunoprecipitation and immunofluorescence analysis confirmed that PAK4 physically interacted with E-cadherin and Cdc42, with evident colocalization of these proteins. In an orthotopic PDAC mouse model, PAK4 knockdown reduced primary tumor burden and prevented malignant ascites, mediated by E-cadherin activation and stabilization. Notably, an inverse correlation between PAK4 and E-cadherin expression was also observed in pancreatic cancer patients’ specimens. Collectively, these findings suggest that PAK4 drives invasive and metastatic phenotypes in PDAC by modulating E-cadherin and that targeting PAK4 may represent a promising therapeutic strategy for PDAC treatment.