Circulating Small Extracellular Vesicles Activate TYRO3 to Drive Cancer Metastasis and Chemoresistance
Autor: | Sung Chul Lim, Youngnam Cho, Y. J. Kim, Seungmin Kang, Kyu Min Kim, Moon-Chang Baek, Keon Wook Kang, Miso Park, Ju Hyun Bae, Sung Baek Jeong, Jin Ki Kim, Dae Won Jun, Yong June Choi, Seung-Hyun Lee, Jiwon Kim, Wankyu Kim, HyungJae Lee, Sung Yun Cho |
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Rok vydání: | 2021 |
Předmět: |
Male
0301 basic medicine Cancer Research RHOA Mice Nude Apoptosis Metastasis Extracellular Vesicles Mice 03 medical and health sciences 0302 clinical medicine Gefitinib Neoplasms Biomarkers Tumor Tumor Cells Cultured medicine Animals Humans Cell Proliferation Mice Inbred BALB C Tumor microenvironment biology Cell growth Chemistry Splenic Neoplasms Liver Neoplasms Receptor Protein-Tyrosine Kinases Cancer MERTK medicine.disease Xenograft Model Antitumor Assays Gene Expression Regulation Neoplastic 030104 developmental biology Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer cell Cancer research biology.protein medicine.drug |
Zdroj: | Cancer Research. 81:3539-3553 |
ISSN: | 1538-7445 0008-5472 |
Popis: | 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. |
Databáze: | OpenAIRE |
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