Abstract 201: Enhanced motility of cancer-associated fibroblasts is mediated by HIF-1α signaling in the lung tumor microenvironment

Abstract Cancer-associated fibroblasts (CAFs) are key contributors to promote cancer progression in the lung tumor microenvironment via interactions with cancer cells and other cell types. In a 3-D culture system, we classified CAFs into two subgroups based on their motility, motile and static CAFs, and isolated these subgroups using the photoconvertible fluorescent protein Dendra2. RNA sequencing and subsequent analyses revealed the upregulation of hypoxia- and glycolysis-related genes in motile CAFs. Activation of HIF-1α increased CAF motility in both mono- and co-culture systems. Knockdown of HIF-1α downstream genes, ALDOA and LDHA, reduced CAF motility. Interestingly, HIF-1α activity and CAF motility were heightened when co-cultured with mesenchymal-like lung cancer cells. Mass spectrometry analysis identified ceruloplasmin (CP) as a secretory protein derived from mesenchymal-like lung cancer cells. Knockdown of CP in mesenchymal-like lung cancer cells attenuated CAF motility in co-culture systems and lung tumor metastasis in a mouse model. Collectively, these findings demonstrated that CAF motility is regulated by HIF-1α signaling, which is modulated by lung cancer cell-derived CP. Citation Format: Jihye Park, Sieun Lee, Jonathan M. Kurie, Young-Ho Ahn. Enhanced motility of cancer-associated fibroblasts is mediated by HIF-1α signaling in the lung tumor microenvironment. [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 201.