Cancer-associated fibroblast-derived stanniocalcin 1 promotes cholangiocarcinoma progression and lymph node metastasis

Cholangiocarcinoma (CCA) is a fibroblast-rich tumor. Lymph node metastasis (LNM) is the main prognostic risk factor for CCA. We determined that stanniocalcin 1 (STC1) is highly expressed in cancer-associated fibroblasts (CAFs) with LNM in CCA. However, the roles of CAFs and STC1 in CCA progression and LNM remain unelucidated. Here, we demonstrated that primary CCA tissues with LNM (LN+CCA) were enriched with more CAFs and lymphatic vessels than those with LN−CCA. LN+ CAFs strongly promoted CCA cell migration, invasion, TrEM, and LNM both in vitro and in vivo. LN+CAFs exhibited significantly higher STC1 expression than LN−CAFs. The in vitro and in vivo results demonstrated that STC1 is mainly responsible for the role of LN+CAFs in promoting CCA malignant behavior. Mechanistic studies demonstrated that STC1 activates integrin αVβ3 and its downstream FAK–YAP pathway. Additionally, we found that targeting STC1 and integrin αVβ3 rescued the pro-tumor effects of CAF on CCA in vitro and in vivo. Therefore, CAF-derived STC1 predicts LNM and is a potential therapeutic target in CCA.