CAF-derived PAI-1 serves as an EGFR ligand and fuels KRAS-mutant pancreatic cancer.

Epidermal growth factor receptor (EGFR) activation contributes to pancreatic cancer etiology, yet anti-EGFR therapy offers minimal clinical benefits in patients with KRAS mutations. We report that plasminogen activator inhibitor-1 (PAI-1) derived from cancer-associated fibroblasts (CAFs) is selectively elevated in KRAS-mutant tumors and functions as a ligand of EGFR, contributing to resistance to anti-EGFR therapy. Ablation of stromal PAI-1 breaks the CAF-tumor interaction, curbing tumor growth and enhancing the therapeutic efficacy of anti-EGFR therapy in both genetically engineered mouse models and patient-derived xenografts. Mechanistically, KRAS mutation in PDAC activates c-Myc to release IL-1α from PDAC cells to stimulate NF-κB signaling in CAFs to turn on the transcription of PAI-1.

PDAC patients with KRAS mutations have higher plasma PAI-1 levels than those with wild-type KRAS.

Our findings reveal a mechanism through which CAFs and tumor cells are regulated by the interaction between PAI-1 secreted by CAFs and EGFR on tumor cells.

Importantly, the newly identified ligand-receptor interaction of PAI-1-EGFR in the tumor microenvironment of pancreatic cancer may open a new avenue for understanding receptor biology.