Excitingly, we find and verify that the absence of the unique domains (NIDO, AMOP, vWD) respectively or simultanously contributes to weaken MUC4-mediated malignant activities, cut off MUC4/Y-triggered malignancy-related positive feedback loops, and down-regulating transcription of the cascading downstream effectors in pancreatic cancer. Here, VWF is linked to pancreatic neoplasm.