Abstract 581: FUT8-mediated fucosylation promotes colorectal cancer growth and metastatic potential via tumor-fibroblast interactions.

Abstract Colorectal cancer (CRC) remains a major clinical burden despite advances in targeted therapies. Aberrant glycosylation, including fucosylation, is increasingly recognized as a key regulator of tumor progression. Analysis of TCGA COAD/READ datasets identified FUT8, the sole enzyme mediating core fucosylation, as significantly elevated in CRC tumors. Its expression pattern and functional activity position FUT8 as a key driver of CRC growth and metastatic traits, including cancer-associated fibroblast (CAF)-mediated tumor-stroma interactions. Transcriptomic and survival analyses were performed using TCGA COAD/READ and the Montefiore-Einstein Comprehensive Cancer Center (MECCC) CRC biobank datasets. FUT8 protein expression was evaluated in paired tumor and normal tissues from MECCC TMAs. Functional characterization was carried out using FUT8 overexpression (OE) and knockdown (KD) CRC cell models, followed by proliferation assays, colony-forming assays, and transwell invasion assays under baseline and CAF-conditioned medium conditions. FUT8 was consistently upregulated in CRC tumors compared with matched normal tissues across TCGA COAD/READ and MECCC transcriptomic cohorts. Stage I/II CRC patients with high FUT8 expression (Q4) exhibited significantly reduced 5-year overall survival compared with the lowest quartile (Q1) (log-rank p = 0.03). In sixteen paired samples from MECCC TMAs, FUT8 protein levels were markedly elevated (about 2-fold) in tumors compared with normal tissues (p < 0.001). Functionally, FUT8 modulation did not alter CRC cell proliferation but robustly regulated aggressive properties: FUT8 OE increased colony size and markedly enhanced transwell invasion, whereas FUT8 KD suppressed both colony formation and invasion. These effects were further amplified in CAF-conditioned medium, suggesting that FUT8 enhances CRC-CAF crosstalk and drives an invasive phenotype. Across transcriptomic analyses and functional assays, FUT8 emerges as a clinically relevant regulator of CRC progression. FUT8 enhances colony formation and invasion independent of proliferation, with its pro-invasive effects strengthened by CAF signaling, establishing FUT8-mediated fucosylation as a driver of CRC aggressiveness. Citation Format: Zimo Huang, Sree K. Kondapuram, Xiang Y. Zheng, Praveen Agrawal, Chaoyuan Kuang. FUT8-mediated fucosylation promotes colorectal cancer growth and metastatic potential via tumor-fibroblast interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 581.