한빛사논문
- 조회1,575
Miso Park1, Ji Won Kim1,2, Kyu Min Kim3,4, Seungmin Kang5,6, Wankyu Kim5, Jin-Ki Kim7, Youngnam Cho8, Hyungjae Lee8, Moon Chang Baek9, Ju-Hyun Bae9, Seung Hyun Lee1, Sung Baek Jeong1,10, Sung Chul Lim11, Dae Won Jun12, Sung Yun Cho13, Yeonji Kim14, Yong June Choi1 and Keon Wook Kang1,*
1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea. 2Division of Hematology and Medical Oncology, University of California, San Francisco, San Francisco, California. 3College of Pharmacy, Chosun University, Gwangju, Republic of Korea. 4Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju, Republic of Korea. 5Department of Life Science, Division of Molecular and Life Sciences, Ewha Womans University, Seoul, Republic of Korea. 6KaiPharm, Seoul, Republic of Korea. 7College of Pharmacy, Hanyang University,
Ansan, Gyeonggi, Republic of Korea. 8Biomarker Branch, National Cancer Center, Gyeonggi, Republic of Korea. 9Department of Biochemistry, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. 10New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea. 11Department of Pathology, College of Medicine, Chosun University, Gwangju, Republic of Korea. 12Department of Internal Medicine, College of Medicine, Hanyang University, Seoul, Republic of Korea. 13Department of Drug Discovery, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea. 14Department of Chemistry, Sungkyunkwan University, Suwon, Republic of Korea.
*Corresponding Author: Keon Wook Kang, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
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.
논문정보
- Research article
- 2021년 07월 (BRIC 등록일 2022-01-12)
- 국내(교신)+국외 연구진
- 의약학 > 약학
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