Claudin‐12‐Expressing Fibroblasts Facilitate Metastatic Spread of Pancreatic Cancer Through Physical Interactions

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.