Pancreatic cancer‐derived small extracellular vesical ezrin activates fibroblasts to exacerbate cancer metastasis through STAT3 and YAP‐1 signaling pathways

Cancer‐associated fibroblasts (CAFs), a major component of the tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC), play an important role in tumorigenesis, metastasis, and chemoresistance. Tumor‐derived small extracellular vesicles (sEVs), which mediate cell‐to‐cell communication between cancer cells and fibroblasts, are also critical for cancer progression and metastasis. However, it remains unclear how PDAC cell‐derived sEVs activate fibroblasts, which contributes to tumor progression. Here, we report that ezrin (EZR) expression in PDAC cell‐derived sEVs (sEV‐EZR) can activate fibroblasts, resulting in increased migration ability and high expression of α‐SMA, PDGFRB, and high production of extracellular matrix in fibroblasts. Reciprocally, sEV‐EZR‐activated fibroblasts enhanced PDAC cell proliferation, invasion, and metastasis to the liver in animal models. Conversely, fibroblasts treated with PDAC cell‐derived sEVs with EZR knockdown resulted in the reduced metastatic ability of PDAC. Mechanistically, we demonstrated that PDAC cell‐derived sEV‐EZR increases the STAT3 and YAP‐1 signaling pathways to induce fibroblast activation, and the activated fibroblasts promote PDAC cell proliferation, invasion, and liver metastasis. Inhibition of the STAT3 and YAP‐1 signaling pathways by gene knockdown can abrogate sEV‐EZR‐induced effects. These findings suggest that targeting the interaction between PDAC cell‐derived sEV‐EZR and fibroblasts is a potential therapeutic strategy for PDAC.