Abstract 5235: Cancer associated fibroblasts-derived SULF1 facilitated carcinogenesis and metastasis of esophageal squamous cell carcinoma

Abstract Cancer-associated fibroblasts (CAFs) play a significant role in creating a supportive environment for tumor growth and progression. Esophageal squamous cell carcinoma (ESCC) ranks as the seventh leading cause of cancer-related deaths globally, characterized by poor clinical outcomes and limited treatment options. CAFs-based therapeutic strategies might benefit ESCC patients. In this study, we utilized single-cell RNA sequencing (scRNA-seq) data from four integrated ESCC cohorts to identify a unique protein, SULF1, secreted by CAFs. Primary human CAFs were isolated from six clinical samples of ESCC and various functional assays, such as transwell migration/invasion and co-culture/co-injection experiments, were conducted to assess the oncogenic or pro-metastatic effects of SULF1-secreting CAFs. Neutralizing antibodies against SULF1 was proposedly used for treatment. Here, we revealed that CAFs exhibited the highest expression levels of SULF1 compared to other cell types based on scRNA-seq data. Immunohistochemistry and immunofluorescence staining confirmed the unique expression of SULF1 in CAFs, particularly in αSMA-rich CAFs within ESCC patient samples. Furthermore, extracellular secretion of SULF1 was elevated in primary human CAFs compared to tumor cells and normal fibroblasts. Co-culture or co-injection of SULF1-knockdown CAFs mixed with tumor cells significantly inhibited tumor growth and metastasis both in vivo and in vitro. Mechanistically, RNA-seq data suggested that CAF-derived SULF1 might activate the TGF-beta and PI3K-AKT signaling pathways, thereby mediating the aggressive behavior of tumor cells. Notably, blocking SULF1-secreted CAFs resulted in suppression of ESCC tumor growth and progression in vivo. Collectively, CAF-secreted SULF1 emerged as a critical mediator in educating the ESCC tumor microenvironment and promoting tumor aggressiveness. Targeting SULF1-expressing CAFs could be viewed as a potential therapeutic strategy for ESCC treatment. Citation Format: Hongyu Zhou, Beilei Liu, Licheng Tan, Baifeng Zhang, Yingchen lyu, Xin-Yuan Guan. Cancer associated fibroblasts-derived SULF1 facilitated carcinogenesis and metastasis of esophageal squamous cell carcinoma [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 5235.