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, we 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.
Bibliographical noteFunding Information:
The authors appreciate members of our laboratories for their kind suggestions. They thank Dr. Sang Kook Lee and Dr. Cheol Ho Jeong for their kind donation of EGFR-TKI–resistant lung cancer cell lines. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (NRF-2018R1A2B2003590). M. Park was a recipient of Basic Science research fellowship through NRF funded by the Ministry of Education (NRF-2020R1A6A3A13070908).
© 2021 American Association for Cancer Research.