Lei Yuqiong, Zhong Cheng, Zhang Jingyuan, Zheng Qi, Xu Yongle, Li Zhoubin, Huang Chenwen, Ren Tao
Department of Respiratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
Department of Lung Transplantation and Thoracic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China.
Oncogene. 2025 Mar;44(11):769-781. doi: 10.1038/s41388-024-03236-5. Epub 2024 Dec 11.
Lung cancer is a fatal complication of idiopathic pulmonary fibrosis (IPF) with a poor prognosis. Current treatments are insufficient in improving the prognosis of lung cancer patients with comorbid idiopathic pulmonary fibrosis (IPF-LC). Senescent fibroblasts, as stromal cells in the tumor microenvironment, influence tumor progression via exosomes. With evidence that fibroblast senescence is an important mechanism of IPF, we investigated the impact of senescent IPF lung fibroblast (diseased human lung fibroblasts, DHLF)-derived exosomes on non-small cell lung cancer (NSCLC). We found DHLF expressed significant senescence markers, and promoted NSCLC proliferation, invasion, and epithelial-mesenchymal transition. Specifically, senescent DHLF showed strong secretion of exosomes, and these exosomes enhanced the proliferation and colony-forming ability of cancer cells. Proteomic analysis showed DHLF-derived exosomes exhibited upregulated senescence-associated secretory phenotype (SASP) factors, notably MMP1, which activates the surface receptor PAR1. Knocking down MMP1 or using PAR1 inhibitors reduced the tumor-promoting effects of DHLF-derived exosomes in vivo and in vitro. Mechanistically, MMP1 acted by activating the PI3K-AKT-mTOR pathway. In conclusion, our results suggest that exosomal MMP1 derived from senescent IPF fibroblasts promotes NSCLC proliferation and colony formation by targeting PAR1 and activating the PI3K-AKT-mTOR pathway. These findings provide a novel therapeutic approach for patients with IPF-LC.
肺癌是特发性肺纤维化（IPF）的一种致命并发症，预后较差。目前的治疗方法在改善合并特发性肺纤维化的肺癌患者（IPF-LC）的预后方面并不充分。衰老的成纤维细胞作为肿瘤微环境中的基质细胞，通过外泌体影响肿瘤进展。有证据表明成纤维细胞衰老为IPF的重要机制，我们研究了衰老的IPF肺成纤维细胞（患病的人肺成纤维细胞，DHLF）来源的外泌体对非小细胞肺癌（NSCLC）的影响。我们发现DHLF表达显著的衰老标志物，并促进NSCLC的增殖、侵袭和上皮-间质转化。具体而言，衰老的DHLF显示出强烈的外泌体分泌，并且这些外泌体增强了癌细胞的增殖和集落形成能力。蛋白质组学分析显示DHLF来源的外泌体表现出衰老相关分泌表型（SASP）因子上调，特别是激活表面受体PAR1的MMP1。敲低MMP1或使用PAR1抑制剂可降低DHLF来源的外泌体在体内和体外的促肿瘤作用。机制上，MMP1通过激活PI3K-AKT-mTOR途径发挥作用。总之，我们的结果表明，衰老的IPF成纤维细胞来源的外泌体MMP1通过靶向PAR1并激活PI3K-AKT-mTOR途径促进NSCLC增殖和集落形成。这些发现为IPF-LC患者提供了一种新的治疗方法。
