Abstract 2586: PAI-1 promotes tumor angiogenesis and metastasis via crosstalk between NSCLC cells and CAFs

Plasminogen activator inhibitor -1 (PAI-1) plays a multifaceted role in the tumor microenvironment, with its high expression correlated with poor prognosis in multiple cancers, including non-small cell lung cancer (NSCLC). Our group’s previous studies have shown that cancer-associated fibroblasts (CAFs) induced PAI-1 in lung cancer cells and that PAI-1 mediated the MET-targeted therapy resistance in NSCLC. In this study, we discovered that CAFs promoted PAI-1 as a secretory protein and its expression in cancer cells themselves and into the conditioned medium by the stimulation of CAF-derived stimulatory factors of transforming growth factor beta-1 (TGFb-1) and -3. Next, we used several lung cancer cell lines with different mutational profiles to assess the effect of PAI-1 in the tumor microenvironment. We investigated the phenotypic changes of lung cancer cells by recombinant human PAI-1 administration and the PAI-1 overexpressed lung cancer cell lines. PAI-1 increased the migratory ability of cancer cells and promoted epithelial to mesenchymal transition (EMT). PAI-1 contributed to tumor progression via the enrichment of EMT, extracellular matrix signaling, and inflammatory and immune responses according to gene set enrichment analysis (GSEA) revealed by the PAI-1 overexpressed lung cancer cells. Moreover, PAI-1 also promoted angiogenesis via the vascular endothelial growth factor (VEGF) pathway supported by the tube formation assay, western blot pathway analysis, and the GSEA. This impact is further validated through vivo study, in which the inhibition of PAI-1 improves the anti-cancer targeted therapy in vivo, where the tumor growth is inhibited by the combination of target therapy and the PAI-1 inhibitor, tiplaxtinin. The tumors from PAI-1 overexpressed lung cancer cells xenograft models also showed high expression of CD31 compared to control, confirming that angiogenesis is being promoted in these tumors. These findings underscore the clinical importance of PAI-1 as an important target for personalized anti-cancer drug therapy. Citation Format: Kazuhiro Okada, Ken Suzawa, Yin Min Thu, Ryunosuke Fujii, Kousei Ishimura, Ryota Fujiwara, Kazuya Hisamatsu, Ryo Yoshichika, Tomoaki Higashihara, Naohiro Hayashi, Fumiaki Mukohara, Mao Yoshikawa, Yuma Fukumoto, Keiichi Date, Hidejiro Torigoe, Kazuhiko Shien, Shinichi Toyooka. PAI-1 promotes tumor angiogenesis and metastasis via crosstalk between NSCLC cells and CAFs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2586.