PLAU orchestrates pancreatic cancer progression via PI3K/AKT/mTORC1-mediated upregulation of MMP2/9 and FSCN1

Pancreatic cancer (PC) is a highly lethal malignancy. PLAU is upregulated in multiple cancers and contributes to tumor progression. Nevertheless, the precise function and molecular mechanism of PLAU in PC progression remain unclear. This study confirmed that PLAU is markedly upregulated in PC and correlated with advanced stage and poor prognosis. PLAU knockdown suppressed PC cell proliferation, migration, invasion, and invadopodia formation and inhibited tumor growth and lung metastasis in vivo. Transcriptomic data from PC tissues and single-cell sequencing showed a significant positive association between PLAU and mTORC1 signaling, MMP2/9, and FSCN1. qRT-PCR and western blot indicated that PLAU knockdown downregulated PI3K/AKT/mTORC1 signaling activity and reduced MMP2/9 and FSCN1 expression, while PLAU overexpression exerted opposite effects. The mTORC1 signaling inhibitor WRX606 reversed PLAU overexpression-mediated upregulation of MMP2/9 and FSCN1. Patient-derived pancreatic cancer organoids (PDPCOs) further validated that PLAU knockdown downregulated mTORC1 signaling, MMP2/9, and FSCN1 and impaired the development and growth of PDPCOs. Collectively, this study revealed that PLAU promotes PC progression by activating PI3K/AKT/mTORC1 signaling to upregulate MMP2/9 and FSCN1, elucidating the specific molecular mechanism by which PLAU drives PC progression and laying the groundwork for further developing novel therapeutic targets and approaches against PC.