Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment

被引：67

作者：

Wang, Zhijun ^{[1
,7
]}

Kim, So Yeon ^{[1
]}

Tu, Wei ^{[1
,8
]}

Kim, Jieun ^{[1
]}

Xu, Alexander ^{[2
,5
]}

Yang, Yoon Mee ^{[1
,9
]}

Matsuda, Michitaka ^{[1
]}

Reolizo, Lien ^{[1
]}

Tsuchiya, Takashi ^{[1
]}

Billet, Sandrine ^{[2
,5
]}

Gangi, Alexandra ^{[3
]}

Noureddin, Mazen ^{[1
,10
]}

Falk, Ben A. ^{[2
,5
]}

Kim, Sungjin ^{[5
]}

Fan, Wei ^{[1
]}

Tighiouart, Mourad ^{[5
]}

You, Sungyong ^{[3
,5
]}

Lewis, Michael S. ^{[2
,4
,6
]}

Pandol, Stephen J. ^{[1
]}

Di Vizio, Dolores ^{[3
,5
]}

Merchant, Akil ^{[2
,5
]}

Posadas, Edwin M. ^{[2
,5
]}

Bhowmick, Neil A. ^{[2
,5
]}

Lu, Shelly C. ^{[1
]}

Seki, Ekihiro ^{[1
,5
]}

机构：

[1] Cedars Sinai Med Ctr, Karsh Div Gastroenterol & Hepatol, Los Angeles, CA 90048 USA

[2] Cedars Sinai Med Ctr, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90048 USA

[3] Cedars Sinai Med Ctr, Dept Surg, Los Angeles, CA 90048 USA

[4] Cedars Sinai Med Ctr, Dept Pathol, Los Angeles, CA 90048 USA

[5] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA

[6] Vet Affairs Greater Los Angeles Hlth Care Syst, Dept Pathol, Los Angeles, CA 90073 USA

[7] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Div Gastroenterol, Wuhan 430022, Peoples R China

[8] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Div Gastroenterol, Wuhan 430030, Peoples R China

[9] Kangwon Natl Univ, Dept Pharm, Chunchon 24341, South Korea

[10] Houston Methodist Hosp, Houston Res Inst, Houston, TX 77030 USA

来源：

CELL METABOLISM | 2023年 / 35卷 / 07期

基金：

美国国家卫生研究院;

关键词：

HIPPO PATHWAY; CANCER; EXPRESSION; RESECTION; DISEASE; YAP; INFILTRATION; STEATOSIS; SURVIVAL; OBESITY;

D O I：

10.1016/j.cmet.2023.04.013

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Liver metastasis is a major cause of death in patients with colorectal cancer (CRC). Fatty liver promotes liver metastasis, but the underlying mechanism remains unclear. We demonstrated that hepatocyte-derived extracellular vesicles (EVs) in fatty liver enhanced the progression of CRC liver metastasis by promoting oncogenic Yes-associated protein (YAP) signaling and an immunosuppressive microenvironment. Fatty liver upregulated Rab27a expression, which facilitated EV production from hepatocytes. In the liver, these EVs transferred YAP signaling-regulating microRNAs to cancer cells to augment YAP activity by suppressing LATS2. Increased YAP activity in CRC liver metastasis with fatty liver promoted cancer cell growth and an immunosuppressive microenvironment by M2 macrophage infiltration through CYR61 production. Patients with CRC liver metastasis and fatty liver had elevated nuclear YAP expression, CYR61 expression, and M2 macrophage infiltration. Our data indicate that fatty liver-induced EV-microRNAs, YAP signaling, and an immunosuppressive microenvironment promote the growth of CRC liver metastasis.

引用

页码：1209 / 1226.e13

页数：32

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