Abstract LB320: Runx2 as a key transcription factor regulating contractility and extracellular matrix remodeling in abnormally activated fibroblasts: Implications for tumorigenesis and keloid pathogenesis

Abstract

Abstract Cancer associated fibroblasts (CAFs) express a variety of cytokines and factors that activate and contribute to pathways that favor tumorigenesis. CAFs disrupt normal cellular functions, such as cell cycle regulation and cell death including apoptosis, or signal certain types of cells to abnormally activate pro-tumor activities. In addition, when it is abnormally activated, it is characterized by increased collagen deposition and more contractility. Likewise, This pattern of abnormal activation is often observed in keloid disease. Keloid constitutes an abnormal fibroproliferative wound healing response with excessive collagen deposition causing abnormal wound healing. To better understand the CAF subtypes with abnormal activation and cancer-promoting properties and the subtypes of keloid fibroblasts with similar activation properties, it is essential to find the master transcription factors (TFs) that determine their identity. To identify functionally important TFs in abnormal CAFs and keloid fibroblasts, we analyzed H3K27ac ChIP-seq of CAFs and keloid fibroblasts and observed that Runx2 significantly enriched the two types of abnormal fibroblasts.To investigate the biological function of Runx2 , we established CAFs from colon cancer patients and performed ShRNA-mediated knockdown of the RUNX2 gene. We confirmed that knockdown of RUNX2 in CAFs suppressed the migration or invasion of cancer cells. Additionally, using a gel contraction assay, we confirmed that fibroblast contractility was significantly reduced by RUNX2 knockdown. Similarly, in keloid fibroblasts, it was confirmed that the migration and gel contraception abilities of fibroblasts were significantly reduced following knockdown of RUNX2 [A1] gene. Last but not least, expression of ECM elements, such as collagens and fibronectin, were significantly as a result of the knockdown of the RUNX2 gene in both abnormally activated fibroblasts. To conclude, we believe that Runx2 acts as a key TF that maintains the contractility and ECM remodeling ability of abnormally activated fibroblasts. Our findings indicate that Runx2 is a attractive therapeutic target not only for pro-tumorigenesis in the cancer microenvironment, but also for keloid fibroblasts. Citation Format: Keun-Woo Lee, Insuk Sohn, Seok-Hyung Kim, So-Young Yeo. Runx2 as a key transcription factor regulating contractility and extracellular matrix remodeling in abnormally activated fibroblasts: Implications for tumorigenesis and keloid pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB320.