Extracellular vesicles secreted by cancer-associated fibroblasts drive non-invasive cancer cell progression to metastasis via TGF-β signalling hyperactivation

Teixeira, A.F.; Wang, Y.H.; Iaria, J.; Dijke, P. ten; Zhu, H.J. (2025)

Article / Letter to editor

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-beta signalling in tumour cells. Metastasis is abolished by genetically targeting CAF-sEV secretion and consequent reduction of TGF-beta signalling in cancer cells. Pharmacological treatment with dimethyl amiloride (DMA) decreases CAFs' sEV secretion, reduces TGF-beta 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.

• cancer-associated fibroblasts
• circulating tumour cells
• extracellular vesicles
• metastasis
• TGF-beta
• therapy
• tumour microenvironment

• All authors: Teixeira, A.F.; Wang, Y.H.; Iaria, J.; Dijke, P. ten; Zhu, H.J.
• Date: 2025-03-01
• Journal: Journal of Extracellular Vesicles
• Volume: 14
• Issue: 3
• DOI: doi:10.1002/jev2.70055