Extracellular Vesicles Secreted by Cancer‐Associated Fibroblasts Drive Non‐Invasive Cancer Cell Progression to Metastasis via TGF‐β Signalling Hyperactivation

ABSTRACT Metastasis is the leading cause of cancer‐related deaths. Cancer‐associated fibroblasts (CAFs) are abundant components within the tumour microenvironment, playing critical roles in metastasis. Although increasing evidence supports a role for small extracellular vesicles (sEVs) in this process, their precise contribution and molecular mechanisms remain unclear, compromising the development of antimetastatic therapies. Here, we establish that CAF‐sEVs drive metastasis by mediating CAF‐cancer cell interaction and hyperactivating TGF‐β signalling in tumour cells. Metastasis is abolished by genetically targeting CAF‐sEV secretion and consequent reduction of TGF‐β signalling in cancer cells. Pharmacological treatment with dimethyl amiloride (DMA) decreases CAFs’ sEV secretion, reduces TGF‐β signalling levels in tumour cells and abrogates metastasis and tumour self‐seeding. This work defines a new mechanism required by CAFs to drive cancer progression, supporting the therapeutic targeting of EV trafficking to disable the driving forces of metastasis.