CAF-derived PAI-1作为EGFR配体并为KRAS-突变型胰腺癌症提供燃料
CAF-derived PAI-1 serves as an EGFR ligand and fuels KRAS-mutant pancreatic cancer.
摘要(中文译文)
表皮生长因子受体（EGFR）的激活促进胰腺癌的发生，然而抗EGFR治疗对携带KRAS突变的患者临床获益甚微。我们发现，来源于癌相关成纤维细胞（CAFs）的纤溶酶原激活物抑制剂-1（PAI-1）在KRAS突变肿瘤中选择性升高，并作为EGFR的配体发挥作用，参与抗EGFR治疗的耐药。清除基质PAI-1可打破CAF与肿瘤之间的相互作用，在基因工程小鼠模型和患者来源异种移植瘤中均能抑制肿瘤生长并增强抗EGFR治疗的疗效。机制上，胰腺导管腺癌（PDAC）中的KRAS突变激活c-Myc，促使PDAC细胞释放IL-1α，进而刺激CAFs中的NF-κB信号通路，启动PAI-1的转录。携带KRAS突变的PDAC患者血浆PAI-1水平高于KRAS野生型患者。我们的研究揭示了CAFs分泌的PAI-1与肿瘤细胞上EGFR之间的相互作用调控CAFs与肿瘤细胞的机制。重要的是，在胰腺癌肿瘤微环境中新发现的PAI-1-EGFR配体-受体相互作用，可能为理解受体生物学开辟新的途径。
Abstract
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.
如何引用
AMA
Yu Wang, Chao Liu, Song Gao, Bo Wang, Hongwei Wang, Zijian Shi, et al. CAF-derived PAI-1 serves as an EGFR ligand and fuels KRAS-mutant pancreatic cancer.. Nature communications. 2026; doi:10.1038/s41467-026-75132-3.
APA
Yu Wang, Chao Liu, Song Gao, Bo Wang, Hongwei Wang, Zijian Shi, et al (2026). CAF-derived PAI-1 serves as an EGFR ligand and fuels KRAS-mutant pancreatic cancer.. Nature communications. https://doi.org/10.1038/s41467-026-75132-3
GB/T 7714
Yu Wang, Chao Liu, Song Gao, Bo Wang, Hongwei Wang, Zijian Shi, et al. CAF-derived PAI-1 serves as an EGFR ligand and fuels KRAS-mutant pancreatic cancer.[J]. Nature communications, 2026 doi:10.1038/s41467-026-75132-3.
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