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

doi:10.1158/0008-5472.CAN-20-3320

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

Department of Life Science

Research output: Contribution to journal › Article › peer-review

15 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 language	English
Pages (from-to)	3539-3553
Number of pages	15
Journal	Cancer Research
Volume	81
Issue number	13
DOIs	https://doi.org/10.1158/0008-5472.CAN-20-3320
State	Published - 1 Jul 2021

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Publisher Copyright:
© 2021 American Association for Cancer Research.

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Park, M., Kim, J. W., Kim, K. M., Kang, S., Kim, W., Kim, J. K., Cho, Y., Lee, H., Baek, M. C., Bae, J. H., Lee, S. H., Jeong, S. B., Lim, S. C., Jun, D. W., Cho, S. Y., Kim, Y., Choi, Y. J., & Kang, K. W. (2021). Circulating small extracellular vesicles activate tyro3 to drive cancer metastasis and chemoresistance. Cancer Research, 81(13), 3539-3553. https://doi.org/10.1158/0008-5472.CAN-20-3320

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title = "Circulating small extracellular vesicles activate tyro3 to drive cancer metastasis and chemoresistance",

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.",

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

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doi = "10.1158/0008-5472.CAN-20-3320",

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T1 - Circulating small extracellular vesicles activate tyro3 to drive cancer metastasis and chemoresistance

AU - Park, Miso

AU - Kim, Ji Won

AU - Kim, Kyu Min

AU - Kang, Seungmin

AU - Kim, Wankyu

AU - Kim, Jin Ki

AU - Cho, Youngnam

AU - Lee, Hyungjae

AU - Baek, Moon Chang

AU - Bae, Ju Hyun

AU - Lee, Seung Hyun

AU - Jeong, Sung Baek

AU - Lim, Sung Chul

AU - Jun, Dae Won

AU - Cho, Sung Yun

AU - Kim, Yeonji

AU - Choi, Yong June

AU - Kang, Keon Wook

PY - 2021/7/1

Y1 - 2021/7/1

N2 - 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.

AB - 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.

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SN - 0008-5472

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ER -

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

Abstract

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