Claudin‐12‐Expressing Fibroblasts Facilitate Metastatic Spread of Pancreatic Cancer Through Physical Interactions
- 1the First Affiliated Hospital of Zhengzhou University
- 2Charité—Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin and Humboldt‐Universität zu Berlin
Abstract
Claudins (CLDNs), as major components of tight junctions in epithelial cells, are emerging as attractive non‐mutant targets for controlling the growth and metastasis of various cancers. However, the mechanisms by which CLDNs modulate tumor progression remain largely unclear. Here, we unexpectedly found that CLDN12 is expressed in cancer‐associated fibroblasts (CAFs), which are generally not considered tight junction‐forming cells. CLDN12 expression in fibroblasts increased their motility and, importantly, promoted direct adhesion to pancreatic cancer cells through homophilic CLDN12–CLDN12 interactions. This CLDN12‐dependent physical interaction between fibroblasts and tumor cells markedly enhanced cancer cell invasion. Moreover, TGF‐β produced by cancer cells further induced the upregulation of CLDN12 expression in fibroblasts. In vivo, CLDN12‐positive fibroblasts facilitated distant metastasis of pancreatic cancer to liver and diaphragm. Targeting CLDN12 with the synthetic peptide C12‐pm efficiently decreased the liver metastasis of pancreatic cancer. Taken together, these findings reveal a previously unrecognized role of CLDN12‐expressing fibroblasts in promoting pancreatic cancer metastasis through direct physical interactions with tumor cells and highlight CLDN12‐mediated interactions as a potential therapeutic target for metastatic pancreatic cancer.
Related
- Spatial multi-omics resolve epithelium-fibroblast gradients and highlight NESTIN-NOTCH1-expressing subepithelial fibroblasts during human pancreatic tumorigenesis
- POSTN-expressing cancer-associated fibroblasts: roles in the tumor microenvironment and clinical implications
- From CAF subtypes to clinically relevant states: cancer-associated fibroblasts in pancreatic ductal adenocarcinoma
- HER3 mediates metabolic reprogramming in metastatic colorectal and pancreatic cancer
- Combined halp and GRIm scores for risk stratification in metastatic pancreatic ductal adenocarcinoma
BibTeX
@article{li2026claudin12expressing,
title = {{Claudin‐12‐Expressing Fibroblasts Facilitate Metastatic Spread of Pancreatic Cancer Through Physical Interactions}},
author = {Qingcui Li and Xiangjing Miao and Yuanyuan Yang and Ruoyang Chen and Qingqing Fang and Xixi Duan and Xiaohan Lou and Xiaohan Yao and Lijing Zhang and Rainer Glauben and Zhihai Qin and Chen Ni},
journal = {MedComm},
year = {2026},
month = oct,
doi = {10.1002/mco2.71114},
url = {https://europepmc.org/article/PMC/PMC13722954},
note = {CC BY},
}
RIS
TY - JOUR
TI - Claudin‐12‐Expressing Fibroblasts Facilitate Metastatic Spread of Pancreatic Cancer Through Physical Interactions
AU - Qingcui Li
AU - Xiangjing Miao
AU - Yuanyuan Yang
AU - Ruoyang Chen
AU - Qingqing Fang
AU - Xixi Duan
AU - Xiaohan Lou
AU - Xiaohan Yao
AU - Lijing Zhang
AU - Rainer Glauben
AU - Zhihai Qin
AU - Chen Ni
PY - 2026
DA - 2026/10/31
JO - MedComm
DO - 10.1002/mco2.71114
UR - https://europepmc.org/article/PMC/PMC13722954
AB - Claudins (CLDNs), as major components of tight junctions in epithelial cells, are emerging as attractive non‐mutant targets for controlling the growth and metastasis of various cancers. However, the mechanisms by which CLDNs modulate tumor progression remain largely unclear. Here, we unexpectedly found that CLDN12 is expressed in cancer‐associated fibroblasts (CAFs), which are generally not considered tight junction‐forming cells. CLDN12 expression in fibroblasts increased their motility and, importantly, promoted direct adhesion to pancreatic cancer cells through homophilic CLDN12–CLDN12 interactions. This CLDN12‐dependent physical interaction between fibroblasts and tumor cells markedly enhanced cancer cell invasion. Moreover, TGF‐β produced by cancer cells further induced the upregulation of CLDN12 expression in fibroblasts. In vivo, CLDN12‐positive fibroblasts facilitated distant metastasis of pancreatic cancer to liver and diaphragm. Targeting CLDN12 with the synthetic peptide C12‐pm efficiently decreased the liver metastasis of pancreatic cancer. Taken together, these findings reveal a previously unrecognized role of CLDN12‐expressing fibroblasts in promoting pancreatic cancer metastasis through direct physical interactions with tumor cells and highlight CLDN12‐mediated interactions as a potential therapeutic target for metastatic pancreatic cancer.
SN - 2688-2663
ER -