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Circulating Small Extracellular Vesicles Activate TYRO3 to Drive Cancer Metastasis and Chemoresistance
- Title
- Circulating Small Extracellular Vesicles Activate TYRO3 to Drive Cancer Metastasis and Chemoresistance
- Authors
- Park, Miso; Kim, Ji Won; Kim, Kyu Min; Kang, Seungmin; Kim, Wankyu; Kim, Jin-Ki; Cho, Youngnam; Lee, Hyungjae; Baek, Moon Chang; Bae, Ju-Hyun; Lee, Seung Hyun; Jeong, Sung Baek; Lim, Sung Chul; Jun, Dae Won; Cho, Sung Yun; Kim, Yeonji; Choi, Yong June; Kang, Keon Wook
- Ewha Authors
- 김완규
- SCOPUS Author ID
- 김완규
- Issue Date
- 2021
- Journal Title
- CANCER RESEARCH
- ISSN
- 0008-5472
1538-7445
- Citation
- CANCER RESEARCH vol. 81, no. 13, pp. 3539 - 3553
- Publisher
- AMER ASSOC CANCER RESEARCH
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- Abstract
- 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. Significance: These findings demonstrate that circulating extracellular vesicles are a novel driver in migration and survival of aggressive cancer cells via TYRO3 activation.
- DOI
- 10.1158/0008-5472.CAN-20-3320
- Appears in Collections:
- 자연과학대학 > 생명과학전공 > Journal papers
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