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

Abstract

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.

Pancreatic cancer and exosomes: role in progression, diagnosis, monitoring, and treatment

“…A study showed that exosomes derived from hypoxic PCCs by transferring miR-301a-3p to macrophages stimulate their polarization to M2 phenotype through the PTEN/PI3Kγ pathway ( 90 ). It has also been shown that exosomes derived from pancreatic tumor cells enriched with ezrin after inducing M2 polarization can increase tumor metastasis to the liver ( 91 ). On the other hand, when M2 macrophages are found in the tumor site, they can help tumor expansion by producing exosomes ( 92 ).…”

Exosome-mediated cell–cell communication within pancreatic cancer tumor microenvironment: a narrative review

“…[61] In addition to KRAS, PCCs also transmitted exosomal Ezrin to TAMs and accelerated their M2 polarization. [62] Under hypoxia, PCCs secreted exosomal miR-301a-3p and promoted M2 polarization of TAMs as well through activating PTEN/PI3K signaling pathway. [63] However, PCCs transfected with miR-155 and miR-125b2 could release exosomes rich in these 2 microRNAs, transforming immunosuppressive M2 TAMs to M1 phenotype with anticancer properties.…”