Abstract 5234: A novel strategy to inhibit colorectal cancer liver metastasis by targeting plasminogen activator inhibitor-1 in liver stromal cells

Abstract Liver metastasis significantly contributes to mortality in colorectal cancer (CRC) patients, highlighting the urgent need for more effective therapeutic strategies. CRC liver metastasis develops within a complex tumor microenvironment that promotes cancer cell colonization and growth. The liver’s supportive role is well described in Paget's "seed and soil" hypothesis. It illustrates how metastatic cancer cells (the "seeds") spread and proliferate in a compatible microenvironment (the "soil"), which includes liver stromal cells. These stromal cells release various factors that aid tumor progression, making it crucial to understand these molecular interactions.This study aims to elucidate the contribution of liver stromal cell-derived factors in CRC metastasis and identify potential therapeutic targets. Using both in vivo and in vitro coculture systems, we found that plasminogen activator inhibitor-1 (PAI-1), a protein produced by liver stromal cells, significantly promotes CRC cell proliferation. Mechanistically, PAI-1 enhances CRC cell survival and proliferation by activating the Akt signaling pathway, which regulates key cellular processes. In xenograft models, therapeutically inhibiting PAI-1 markedly reduced liver metastasis. Furthermore, experiments using PAI-1 knockout mice showed a substantial decrease in metastatic burden, underscoring PAI-1's pivotal role in CRC progression.These results establish PAI-1 as a promising therapeutic target. Its inhibition could potentially reduce CRC liver metastasis and improve patient outcomes. Given the complex nature of tumor-stromal interactions, our findings provide critical insights into targeting liver stromal proteins for effective CRC metastatic treatment. Citation Format: Tomokazu Ohishi, Yukinari Kato, Mika K. Kaneko, Shun-ichi Ohba, Akiko Harakawa, Hiroyuki Inoue, Junjiro Yoshida, Daisuke Tatsuda, Tomoko Nakanishi, Masanori Hatakeyama, Manabu Kawada. A novel strategy to inhibit colorectal cancer liver metastasis by targeting plasminogen activator inhibitor-1 in liver stromal cells [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 5234.