Claudin-18.2 mediated interaction of gastric Cancer cells and Cancer-associated fibroblasts drives tumor progression

Sep 21, 2026

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Claudin-18.2 (CLDN18.2) is investigated as a therapeutic target in gastric cancer, focusing on how it regulates tumor progression through communication with cancer-associated fibroblasts (CAFs). The study analyzes 185 gastric cancer patients stratified by immunohistochemistry-defined CLDN18.2 expression, and uses in vitro adhesion and in vivo lung colonization models after CLDN18.2 modulation. RNA sequencing and in vivo protein-proximity labeling reveal CAF-driven adhesion and metastasis signaling, identifying S100A4 as a CAF marker interacting with CLDN18.2.

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Abstract

Introduction

Liu et al. Cell Communication and Signaling (2024) 22:27 [https://doi.org/10.1186/s12964-023-01406-8](https://doi.org/10.1186/s12964-023-01406-8) Cell Communication and Signaling RESEARCH Open Access Claudin-18.2 mediated interaction of gastric Cancer cells and Cancer-associated fibroblasts drives tumor progression Shengde Liu1†, Zizhen Zhang1†, Lei Jiang1, Miao Zhang1, Cheng Zhang1* and Lin Shen1* Abstract Background Claudin-18 .2 (CLDN18 . 2) has emerged as an alluring therapeutic target against gastrointestinal tumorsin 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 metastasisrelated 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 CAFsin promoting gastric cancer progression and embolism, thereby providing insight into potential therapeutic avenues for CLDN18 .2 positive cancers. Keywords Gastric cancer, CLDN18 . 2, cancer-associated fibroblasts, Metastasis, Adhesion, S100A4 †Shengde Liu and Zizhen Zhang contributed equally to this work. *Correspondence: Cheng Zhang [qenya_z@bjmu.edu.cn](qenya_z@bjmu.edu.cn)[ ](qenya_z@bjmu.edu.cn)Lin Shen [shenlin@bjmu.edu.cn](shenlin@bjmu.edu.cn) 1 Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China Introduction Gastric cancer (GC) ranks as the fifth most frequently occurring cancer globally and is associated with high incidence and mortality rates [1]. Despite significant progress in diagnostic and treatment modalities, the prognosis of GC patients remains poor, emphasizing the pressing need to identify new therapeutic targetsand effective drugs to improve patient outcomes [2]. Combining such treatments with personalized medicine © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not incl

FAQs

What is CLDN18.2’s proposed role in gastric cancer?

CLDN18.2 is presented as a therapeutic target whose regulatory functions in gastric cancer involve interactions with cancer-associated fibroblasts and influence tumor progression.

How was the study designed to evaluate CLDN18.2-mediated interactions?

The work combines patient cohort analysis stratified by CLDN18.2 expression with in vitro adhesion models and in vivo lung colonization models, plus RNA sequencing and in vivo protein-proximity labeling to define mechanisms.

What molecular marker linked CAFs to CLDN18.2-mediated progression?

S100A4 is identified as a distinctive CAF marker that interacts with CLDN18.2 and enhances gastric cancer progression.

Sep 21, 2026

Uploaded by Jiven