Rationale:Aberrant glycosylation has been known to regulate cancer cell trafficking via promoting intravascular adhesion during metastasis. Clinicopathological studies have also shown a strong correlation between aberrant glycosylation and invasive/metastatic potentials of human cancers. However, the major glycosylation enzymes that drive lung cancer metastases and the signaling networks involved in the process remain incompletely understood.

Methods:We identified fucosyltransferase 4 (FUT4) as a strong predictor of patient prognosis from two independent cohorts of patients with NSCLC (TCGA and NTUH). We analyzed functional roles of FUT4 through over-expression and knock-down studies using lung cancer cell lines in vitro. Metastatic and homing potentials of FUT4-overexpressed and/or knockdown cells were evaluated in vivo in immunodeficient mice. Genome-wide RNA-seq and MS-based immune-precipitation proteomics were performed to study molecular signaling networks.

Results: High expressions of FUT4 were associated with poor survivals in lung adenocarcinomas (p= 0.000681). FUT4-overexpressed lung cancer cells showed significantly increased migration, invasion, and adhesion abilities in vitro, as well as enhanced homing ability to the lungs in vivo. FUT4-overexpressedcells displayed typical characteristics of epithelial-to-mesenchymal transition (EMT) in a protein level-dependent manner. Lewis X and AAL antigens were significantly up-regulated in FUT4-overexpressedcells, which facilitated binding to E-, L- and P-selections. GSEA of RNA-seq data revealed the enrichment of metastasis-related signaling, especially in EGF and TGF-β signalings. Molecularly, FUT4 enhanced EGFR/TGFBR signaling through glycosylation of TGFBR receptors, which lead to increased binding affinity between ligands and its receptors.

Conclusion: FUT4 promoted metastasis through enhancing mesenchymal phenotype mediated by glycosylated EGFR/TGFBR signaling, and through increasing binding affinity of cancer cells to selectins. High levels of FUT4 in tumor tissues significantly correlate with poor prognosis in NSCLC patients. Our study not only provided new insights into the role of FUT4 on molecular signaling as a potential therapeutic target, but also identified FUT4 as a prognostic marker in NSCLC.

Note: This abstract was not presented at the meeting.

Citation Format: Hsuan-Hsuan Lu, Yi-Hsiu Juan, Rueyhung Roc Weng, Shu-Yung Lin, Yen-Wei Chen, Hsin-Han Hou, Zheng-Ci Hung, Yi-Jhen Huang, Tsai-Yu Yang, Yi-Chieh Wu, Giovanni Audrey Oswita, Jin-Yuan Shih, Hsing-Chen Tsai, Chong-Jen Yu. Fucosyltransferase 4-mediated aberrant glycosylation and cell signaling networks promote lung cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1111.