Abstract 3888: N-glycosylation-defective IL6 activates the SRC-YAP-SOX2 signaling to potentiate metastasis and TKI resistance in NSCLC

Abstract

Abstract The IL6-GP130-STAT3 signaling pathway facilitates lung cancer progression and resistance to tyrosine kinase inhibitors. Although glycosylation alters the stability of GP130 receptor, its effect on the ligand IL6 remains unclear. In this study, we found that N-glycosylated IL6 primarily triggers JAK-STAT3 signaling and prolongs STAT3 phosphorylation, whereas N-glycosylation-defective IL6 (DeNG-IL6) induces shortened STAT3 activation and changes the downstream signaling preference for the SRC-YAP-SOX2 axis. This signaling shift promoted epithelial plasticity in vitro and metastasis in vivo, which were suppressed by specific inhibitors and shRNAs targeting SRC, YAP, and SOX2. EGFR TKI-resistant lung cancer cells secrete high levels of DeNG-IL6 via reduced N-glycosyltransferase gene expression and showed SRC-YAP activation. DeNG-IL6 contributes to drug resistance, as confirmed by in silico analysis of cellular and clinical transcriptomes, and signal expression in patient specimens. In summary, cell behaviors can be altered by modifying the N-glycosylation of IL6, and the glycosylation status of circulating IL6 might be a promising biomarker for monitoring the dynamics of lung cancer evolution. Citation Format: Chun Hua Hung, Shang-Yin Wu Wu, Hsuan-Heng Yeh Yeh, Chien-Chung Lin, Wu-Chou Su. N-glycosylation-defective IL6 activates the SRC-YAP-SOX2 signaling to potentiate metastasis and TKI resistance in NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3888.