TGF-β and extracellular vesicles in the tumor microenvironment

Abstract

This PhD thesis explores the intricate role of the tumor microenvironment (TME), focusing on how cellular interactions and extracellular vesicles (EVs) contribute to cancer progression. It highlights cancer-associated fibroblasts (CAFs) as key modulators of the TME, emphasizing their heterogeneity, plasticity, and ability to promote tumor growth, immune evasion, and resistance to therapy. A central focus is the dual role of Transforming Growth Factor Beta (TGF-ß), which not only activates CAFs but also influences EV secretion and function. The thesis demonstrates that TGF-ß reduces EV release in breast cancer cells by downregulating RAB27A/B, alters EV cargo, and reprograms EV-mediated communication. Furthermore, it shows that EVs from TGF-ß-activated CAFs induce further CAF activation and suppress CD8+ T cell activity, largely through surface-bound proteins that enhance TGF-ß signaling in recipient cells. These findings reveal a feedback loop in which TGF-ß shapes the TME through EV-mediated intercellular signaling, offering insights into potential therapeutic targets.