Small extracellular vesicle-packaged TGFS1 promotes the reprogramming of normal fibroblasts into cancer-associated fibroblasts by regulating fibronectin in head and neck squamous cell carcinoma

Tumor development and progression hinge upon ongoing coevolution and crosstalk with the tumor microenvironment. In particular, fibroblasts in the tumor stroma are coopted to support tumor growth and survival through interactions with tumor cells. Despite their significant importance, there is no consensus on the origin of cancer-associated fibroblasts (CAFs) in head and neck squamous cell carcinoma (HNSCC). In this study, we demonstrated that small extracellular vesicle (sEV)-packaged TGFS1 can reprogram normal fibroblasts (NFs) into CAFs both in vitro and in vivo. Mechanistically, TGFS1 in sEV activated NFs by regulating fibronectin, rather than modulating the canonical TGFS-Smad signal pathway. Furthermore, TGFS1 and fibronectin are related to HNSCC clinicopathologic features. Plasma sEV TGFS1 may serve as a potential diagnostic biomarker for HNSCC. This hitherto unknown mechanism of reprogramming of NFs into CAFs by a unique pathway has major implications for underlying cancer-recruited stroma responses.