Claudin-18.2 mediated interaction of gastric Cancer cells and Cancer-associated fibroblasts drives tumor progression
Shengde Liu, Zizhen Zhang, Lei Jiang, Miao Zhang, Cheng Zhang, Lin Shen
Abstract
BACKGROUND: Claudin-18.2 (CLDN18.2) has emerged as an alluring therapeutic target against gastrointestinal tumors in recent years. However, a thorough understanding of its regulatory mechanism in gastric cancer remains elusive. METHODS: We presented a comprehensive study comprising 185 gastric cancer patients, which included 112 cases with high CLDN18.2 expression and 73 cases with low CLDN18.2 expression as determined by immunohistochemistry. After overdressed CLDN18.2 in AGS and NUGC4 cell lines, we elucidated the functions of CLDN18.2 in connecting gastric cancer cells and cancer-associated fibroblasts (CAFs) through an in vitro adhesion models and in vivo lung colonization models. The molecular mechanism underlying CLDN18.2-mediated interaction between gastric cancer cells and CAFs was identified through RNA sequencing and protein-proximity labeling techniques in vivo. RESULTS: In our own cohort, a correlation was observed between high levels of CLDN18.2 expression and advanced cancer stage, poor prognosis, and heightened infiltration of CAFs. We elucidated a pivotal role of CLDN18.2 in mediating adhesion between gastric cancer cells and CAFs, which leads to the adhesion of cancer cells to stroma tissue and facilitates the clustering of cancer cells and CAFs into embolus, enhancing gastric cancer's metastatic progression and the risk of embolic death. Mechanistically, it was discovered that CAFs can activate adhesion and metastasis-related signaling pathways in CLDN18.2-positive gastric cancer cells. Furthermore, using an in vivo protein-proximity labeling approach, we identified S100 calcium binding protein A4 (S100A4) as a distinctive marker of CAFs that interacts with CLDN18.2 to enhance gastric cancer progression. CONCLUSIONS: Our findings illuminated the role of the CLDN18.2-mediated interaction between cancer cells and CAFs in promoting gastric cancer progression and embolism, thereby providing insight into potential therapeutic avenues for CLDN18.2 positive cancers. Video Abstract.