Tumor-derived extracellular vesicles-mediated oxidative stress transfer activates glycometabolic reprogramming of...

In the adverse tumor microenvironment excessive tumor cell proliferation is accompanied by massive reactive oxygen species (ROS) production. Though tumor-derived extracellular vesicles (TEVs) have confirmed roles in cancer-associated fibroblast (CAF) interactions, the intercellular ROS transfer mechanism and its specific role in tumor-stroma communication remain unclear.

Human gingival fibroblasts (HGFs), paracancerous normal fibroblasts (PNFs) and CAFs were isolated from volunteers' healthy gingival tissues and 6 OSCC patients. In vitro, autophagy and glycometabolism levels in PNFs/CAFs and HGFs/TEVs-treated HGFs were assessed via immunofluorescence and Western blot; autophagy was blocked or activated to explore its effect on glycometabolism; flow cytometry was used to detect if TEVs trigger fibroblast autophagy and glycolysis via ROS transfer. In vivo, xenograft models were established to validate TEVs' effect.

CAFs had higher autophagy than PNFs. Autophagy inhibitors reduced TEVs-induced autophagy-dependent glycometabolic reprogramming, while autophagy activation enhanced CAF glycolysis. Moreover, TEV-transferred ROS drove such reprogramming via autophagy-dependent mechanisms and the HIF-1α/PFKFB3 axis. In vivo, TEVs consistently promoted autophagy and glycometabolic reprogramming.

TEVs-induced intercellular ROS transmission and the regulatory role of autophagy in CAF glycometabolic reprogramming offer a novel basis for the oxidative stress transfer model in tumor-stroma crosstalk.