Abstract 4265: ZEB1-regulated hyaluronan network in the lung tumor microenvironment

Abstract In the tumor microenvironment, hyaluronan surrounds neighboring cells as one of the major components of the extracellular matrix and stimulates the epithelial-mesenchymal transition (EMT) of various epithelial cancer cells. However, the mechanism of how the hyaluronic network is formed by cancer cells and regulates cancer progression and metastasis has not been known in detail. Therefore, we investigated the role of the hyaluronan network built-up by cancer cells in regulating cancer progression and metastasis in the tumor microenvironment. Our study demonstrated that ZEB1, an EMT-inducing transcription factor, reconstructs the hyaluronan network to induce the expression of ITIH2, a hyaluronan-binding protein, and hyaluronic acid synthase-2 (HAS2), ZEB1 was also shown to control the isoform switching of CD44, a hyaluronan receptor. ITIH2 knockdown and HAS inhibition reduced the formation of hyaluronan cables and inhibited cancer cell migration and invasion. In addition, the treatment of a specific ITIH2 inhibitor identified through deep learning-based screening suppressed the formation of hyaluronan cables, cell migration, and metastasis. These findings suggest that targeting the hyaluronan network could be a novel strategy for suppressing lung cancer progression and metastasis in the tumor microenvironment. Citation Format: Sieun Lee, Jihye Park, Eun Ju Kim, Seongran Cho, Sungsoo Park, Jonathan M Kurie, Young-Ho Ahn. ZEB1-regulated hyaluronan network in the lung tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4265.