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Three-Dimensional Human Liver-Chip Emulating Premetastatic Niche Formation by Breast Cancer-Derived Extracellular Vesicles

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Title
Three-Dimensional Human Liver-Chip Emulating Premetastatic Niche Formation by Breast Cancer-Derived Extracellular Vesicles
Author(s)
Junyoung Kim; Chaeeun Lee; Inun Kim; Jooyoung Ro; Jungmin Kim; Yoohong Min; Juhee Park; Vijaya Sunkara; Yang-Seok Park; Issac Michael; Young-Ae Kim; Hee Jin Lee; Yoon-Kyoung Cho
Publication Date
2020-11
Journal
ACS NANO, v.14, no.11, pp.14971 - 14988
Publisher
AMER CHEMICAL SOC
Abstract
The liver is one of the most common sites of breast cancer metastasis and is associated with high lethality. Although the interaction between tumor cells and their microenvironment at metastatic sites has been recognized as a key regulator of tumor progression, the underlying mechanism is not fully elucidated. Here, we describe a three-dimensional (3D) microfluidic human liver-on-a-chip (liver-chip) that emulates the formation of a premetastatic niche to investigate the roles of breast cancer-derived extracellular vesicles (EVs) in liver metastasis. We demonstrate that breast cancer-derived EVs activate liver sinusoidal endothelial cells (LSECs) in the liver-chip, inducing endothelial to mesenchymal transition and destruction of vessel barriers. In addition, we show that transforming growth factor β1 (TGFβ1) in breast cancer-derived EVs upregulates fibronectin, an adhesive extracellular matrix protein, on LSECs, which facilitates the adhesion of breast cancer cells to the liver microenvironment. Furthermore, we observed that EVs isolated from triple-negative breast cancer (TNBC) patients with liver metastasis contain higher TGFβ1 levels and induce adhesion of more breast cancer cells to the 3D human liver-chip than do EVs isolated from healthy donors or nonmetastatic TNBC patients. These findings provide a better understanding of the mechanisms through which breast cancer-derived EVs guide secondary metastasis to the liver. Furthermore, the 3D human liver-chip described in this study provides a platform to investigate the mechanisms underlying secondary metastasis to the liver and possible therapeutic strategies.
URI
https://pr.ibs.re.kr/handle/8788114/9000
DOI
10.1021/acsnano.0c04778
ISSN
1936-0851
Appears in Collections:
Center for Soft and Living Matter(첨단연성물질 연구단) > 1. Journal Papers (저널논문)
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