mTOR-driven integrin β4-enriched extracellular vesicles from lenvatinib-resistant hepatocellular carcinoma fuel lung metastasis via fibroblast-niche formation

Tumor-derived extracellular vesicles (EVs) play crucial roles in facilitating the colonization and growth of metastatic cancer cells in distant organs. Nevertheless, the precise mechanisms by which EVs contribute to therapy-resistant cancer dissemination remain poorly understood. In the present study, we aim to investigate how EVs derived from lenvatinib-resistant (LR) hepatocellular carcinoma (HCC) drive lung metastasis and identify potential therapeutic targets for both inhibiting metastasis and overcoming lenvatinib resistance. Using LR HCC models and omics analysis, we demonstrated that LR HCC cells exhibited an enhanced metastatic potential towards the lungs owing to an increased release of EVs. Aberrant activation of mTOR signaling drove EVs secretion from LR cells by impeding the autophagic degradation of multivesicular bodies (MVBs). Furthermore, EVs derived from LR cells exhibited an enrichment of ITGβ4, thereby fostering the pre-metastatic niche (PMN) formation by activating lung fibroblasts via the ITGβ4-laminin interaction and the PI3K-AKT-p65 signaling pathway. Elevated levels of plasma EV-ITGβ4 were observed in LR HCC patients and associated with dismal prognosis. Moreover, inhibition of mTOR signaling using rapamycin impeded lung metastasis and restored the sensitivity to lenvatinib. These findings highlight the role of ITGβ4-enriched EVs released from LR HCC cells in promoting lung metastasis and propose a potential target for combating lung metastasis and overcoming lenvatinib resistance.