Senescent lung fibroblasts in idiopathic pulmonary fibrosis facilitate non-small cell lung cancer progression by secreting exosomal MMP1

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 play a pivotal role within the tumor microenvironment, influencing tumor progression by secreted exosomes. With evidence that fibroblast senescence is an important mechanism of IPF, we sought to investigate the impact of senescent IPF lung fibroblast-derived exosomes on non-small cell lung cancer (NSCLC). Our results show that IPF fibroblasts (diseased human lung fibroblasts, DHLF) express significant senescence markers, promoting NSCLC proliferation, invasion, and epithelial-mesenchymal transition. Specifically, we observed senescent DHLFs secret more exosomes (DHLF-exosomes), which could enhance proliferation and colony-forming ability of cancer cells. Proteomic analysis of DHLF-exosomes identified upregulation of SASP factors, notably MMP1, which activates the surface receptor PAR1. Knocking down MMP1 or using PAR1 inhibitors reduced the tumor-promoting effects of DHLF-exosomes in vivo and in vitro. Mechanistically, MMP1 acted via 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. To elucidate the pro-tumorigenic mechanisms of exosomes derived from IPF lung fibroblasts(DHLF-exo), we performed RNA-seq analysis on SK-MES-1 cells incubated with and without DHLF-exos. The experimental procedure was as follows: SK-MES-1 cells were initially seeded in 6-well plates. On the following day, the medium was replaced with complete medium containing 20 μg/ml DHLF-exos (N=3), while a parallel control group was maintained without exosome supplementation(N=3). After 72 hours of incubation, total RNA was extracted from SK-MES-1 cells, both with and without exosome treatment, using Trizol reagent (Invitrogen). Subsequently, RNA sequencing was performed using the NovaSeq 6000 platform.