Circulating small extracellular vesicles activate tyro3 to drive cancer metastasis and chemoresistance

Miso Park, Ji Won Kim, Kyu Min Kim, Seungmin Kang, Wankyu Kim, Jin Ki Kim, Youngnam Cho, Hyungjae Lee, Moon Chang Baek, Ju Hyun Bae, Seung Hyun Lee, Sung Baek Jeong, Sung Chul Lim, Dae Won Jun, Sung Yun Cho, Yeonji Kim, Yong June Choi, Keon Wook Kang

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish
Pages (from-to)3539-3553
Number of pages15
JournalCancer Research
Volume81
Issue number13
DOIs
StatePublished - 1 Jul 2021

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