The urokinase receptor/uPAR is a major effector of p53 gain-of-function mutations in gemcitabine-treated pancreatic ductal adenocarcinoma.

In pancreatic ductal adenocarcinoma (PDAC), chemotherapy may select for cancer cells with increased capacity for invasion and metastasis. The responsible mechanisms remain incompletely elucidated; however, TP53, which carries gain-of-function (GoF) mutations, has been implicated. PLAUR encodes a cellular receptor, uPAR, which promotes cancer invasion, metastasis, epithelial-mesenchymal transition (EMT), and resistance to chemotherapy. Mining TCGA showed that in PDAC, PLAUR expression is substantially increased and the extent of increase correlates with cancer stage. High PLAUR expression is associated with decreased overall, disease-free, and progression-free survival. PLAUR expression is increased in PDACs with TP53 GoF mutations. In PANC1 and MIA PaCa-2 PDAC cells, which express TP53 GoF mutations, gemcitabine treatment increased PLAUR expression, ERK1/2 activation, and ribosomal S6 kinase phosphorylation in surviving cells. The surviving cells also demonstrated increased migration and invasion. The increase in uPAR abundance was sustained and continued to increase after gemcitabine was withdrawn. Silencing TP53 blocked the gemcitabine-induced increase in uPAR abundance and the associated increases in ERK1/2 activation, cell migration, and invasion. Silencing EGFR did not affect uPAR-promoted ERK1/2 activation, despite the known ability of the EGF Receptor to collaborate with uPAR in activating cell signaling under select circumstances. scRNA-Seq of human PDACs showed that PLAUR expression is increased in specific clusters of malignant epithelial cells post-treatment. High PLAUR expression is associated with increased basal cell-like gene expression signatures, copy number instability, and EMT signatures. Mutated TP53-induced PLAUR expression represents a major pathway by which PDAC treatment may lead to chemotherapy resistance and increased cancer cell aggressiveness.