Hypoxia-induced CD147-enriched migrasomes promote sorafenib resistance in HCC by inducing vasculogenic mimicry via PI3K/AKT/TWIST1 signaling

Conventional anti-angiogenic drugs (AADs) combined with sorafenib have little success in HCC patients, as the formation of hypoxia areas in tumors and vasculogenic mimicry's (VM's) non-responsiveness to AADs. Migrasomes are recently discovered extracellular vesicles produced during cell migration. In this study, the results show that hypoxia-induced migrasomes induce the formation of VM and promote the sorafenib resistance. Further studies reveal that hypoxia-induced migrasomes can be taken up by HCC cells via macropinocytosis, which activates PI3K/AKT/TWIST1 signaling. Moreover, CD147 on the surface of hypoxia-induced migrasomes is identified as a key protein in regulating the signaling pathway. Overall, our findings uncover a previously unrecognized mechanism mediated by hypoxia-induced migrasomes and the formation of VM and provide a new method for preventing SFR. Overall design: RNA-seq profiling of MHCC-97H cells treated for 24 hours with PBS, migrasomes from MHCC-97H cells cultured in normoxia (Normo-Migs), migrasomes from MHCC-97H cells cultured in hypoxia (Hypo-Migs), or migrasomes from CD147 knockout MHCC-97H cells cultured in hypoxia (CD147KO-Migs)