Circulating Small Extracellular Vesicles Activate TYRO3 to Drive Cancer Metastasis and Chemoresistance
- 주제(기타) Oncology
- 설명문(일반) [Park, Miso; Kim, Ji Won; Lee, Seung Hyun; Jeong, Sung Baek; Choi, Yong June; Kang, Keon Wook] Seoul Natl Univ, Coll Pharm, Seoul 08826, South Korea; [Park, Miso; Kim, Ji Won; Lee, Seung Hyun; Jeong, Sung Baek; Choi, Yong June; Kang, Keon Wook] Seoul Natl Univ, Res Inst Pharmaceut Sci, Seoul 08826, South Korea; [Kim, Ji Won] Univ Calif San Francisco, Div Hematol & Med Oncol, San Francisco, CA 94143 USA; [Kim, Kyu Min] Chosun Univ, Coll Pharm, Gwangju, South Korea; [Kim, Kyu Min] Chosun Univ, Coll Nat Sci, Dept Biomed Sci, Gwangju, South Korea; [Kang, Seungmin; Kim, Wankyu] Ewha Womans Univ, Dept Life Sci, Div Mol & Life Sci, Seoul, South Korea; [Kang, Seungmin] KaiPharm, Seoul, South Korea; [Kim, Jin-Ki] Hanyang Univ, Coll Pharm, Ansan, Gyeonggi, South Korea; [Cho, Youngnam; Lee, Hyungjae] Natl Canc Ctr, Biomarker Branch, Gyeonggi, South Korea; [Baek, Moon Chang; Bae, Ju-Hyun] Kyungpook Natl Univ, Sch Med, Dept Biochem, Daegu, South Korea; [Jeong, Sung Baek] Daegu Gyeongbuk Med Innovat Fdn, New Drug Dev Ctr, Daegu, South Korea; [Lim, Sung Chul] Chosun Univ, Coll Med, Dept Pathol, Gwangju, South Korea; [Jun, Dae Won] Hanyang Univ, Coll Med, Dept Internal Med, Seoul, South Korea; [Cho, Sung Yun] Korea Res Inst Chem Technol, Dept Drug Discovery, Daejeon, South Korea; [Kim, Yeonji] Sungkyunkwan Univ, Dept Chem, Suwon, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 AMER ASSOC CANCER RESEARCH
- 발행년도 2021
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000182244
- 본문언어 영어
- Published As http://dx.doi.org/10.1158/0008-5472.CAN-20-3320
초록/요약
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.
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