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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月4日

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  • Yu Wang,
  • Chao Liu,
  • Song Gao,
  • Bo Wang,
  • Hongwei Wang,
  • Zijian Shi,
  • Shunjin Xia,
  • Jiayong Li,
  • Xiaofeng Yao,
  • Xiaofan Guo,
  • Jianwei Zheng,
  • Qianqian Zhou,
  • Zhiqiang Chen,
  • Lei Zheng,
  • Qiang Zhang,
  • Jiang Du,
  • Tianxing Zhou,
  • Zhaoyu Zhang,
  • Weijie Song,
  • Lisha Qi,
  • Yalei Wang,
  • Yuh-Pyng Sher,
  • Min Li,
  • Xuan Zhou,
  • Mien-Chie Hung,
  • Yu Ren,
  • Jihui Hao

摘要

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.