An extracellular vesicular mutant KRAS-associated protein complex promotes lung inflammation and tumor growth

Extracellular vesicles (EVs) contain more than 100 proteins. Whether there are EVs proteins that act as an 'organiser' of protein networks to generate a new or different biological effect from that identified in EV-producing cells has never been demonstrated. Here, as a proof-of-concept, we demonstrate that EV-G12D-mutant KRAS serves as a leader that forms a protein complex and promotes lung inflammation and tumour growth via the Fn1/IL-17A/FGF21 axis. Mechanistically, in contrast to cytosol derived G12D-mutant KRAS complex from EVs-producing cells, EV-G12D-mutant KRAS interacts with a group of extracellular vesicular factors via fibronectin-1 (Fn1), which drives the activation of the IL-17A/FGF21 inflammation pathway in EV recipient cells. We show that: (i), depletion of EV-Fn1 leads to a reduction of a number of inflammatory cytokines including IL-17A; (ii) induction of IL-17A promotes lung inflammation, which in turn leads to IL-17A mediated induction of FGF21 in the lung; and (iii) EV-G12D-mutant KRAS complex mediated lung inflammation is abrogated in IL-17 receptor KO mice. These findings establish a new concept in EV function with potential implications for novel therapeutic interventions in EV-mediated disease processes.

Automated summary

This study demonstrates that a protein in extracellular vesicles (EVs) acts as an organizer of protein networks, promoting lung inflammation and tumor growth through the Fn1/IL-17A/FGF21 pathway. EV-G12D-mutant KRAS was shown to interact with extracellular vesicular factors via fibronectin-1 (Fn1), activating the IL-17A/FGF21 inflammation pathway in recipient cells. These findings provide a new understanding of EV function with potential implications for therapeutic interventions in EV-mediated diseases.