Extracellular vesicles (EV) in the tumor microenvironment have emerged as crucial mediators that promote proliferation, metastasis, and chemoresistance. However, the role of circulating small EVs (csEV) in cancer progression remains poorly understood. In this study, researchers from the Seoul National University report that csEV facilitate cancer progression and determine its molecular mechanism. csEVs strongly promoted the migration of cancer cells via interaction with phosphatidylserine of csEVs. Among the three TAM receptors, TYRO3, AXL, and MerTK, TYRO3 mainly interacted with csEVs. csEV-mediated TYRO3 activation promoted migration and metastasis via the epithelial–mesenchymal transition and stimulation of RhoA in invasive cancer cells. Additionally, csEV–TYRO3 interaction induced YAP activation, which led to increased cell proliferation and chemoresistance. Combination treatment with gefitinib and KRCT-6j, a selective TYRO3 inhibitor, significantly reduced tumor volume in xenografts implanted with gefitinib-resistant non–small cell lung cancer cells. The results of this study show that TYRO3 activation by csEVs facilitates cancer cell migration and chemoresistance by activation of RhoA or YAP, indicating that the csEV/TYRO3 interaction may serve as a potential therapeutic target for aggressive cancers in the clinic.
Circulating extracellular vesicles are a novel driver in migration and survival of aggressive cancer cells
Park M, Kim JW, Kim KM, Kang S, Kim W, Kim JK, Cho Y, Lee H, Baek MC, Bae JH, Lee SH, Jeong SB, Lim SC, Jun DW, Cho SY, Kim Y, Choi YJ, Kang KW. (2021) Circulating small extracellular vesicles activate TYRO3 to drive cancer metastasis and chemoresistance. Cancer Res [Epub ahead of print]. [abstract]