Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment

Zhijun Wang; So Yeon Kim; Wei Tu; Jieun Kim; Alexander Xu; Yoon Mee Yang; Michitaka Matsuda; Lien Reolizo; Takashi Tsuchiya; Sandrine Billet; Alexandra Gangi; Mazen Noureddin; Ben A. Falk; Sungjin Kim; Wei Fan; Mourad Tighiouart; Sungyong You; Michael S. Lewis; Stephen J. Pandol; Dolores Di Vizio; Akil Merchant; Edwin M. Posadas; Neil A. Bhowmick; Shelly C. Lu; Ekihiro Seki

doi:10.1016/j.cmet.2023.04.013

Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment

Zhijun Wang, So Yeon Kim, Wei Tu, Jieun Kim, Alexander Xu, Yoon Mee Yang, Michitaka Matsuda, Lien Reolizo, Takashi Tsuchiya, Sandrine Billet, Alexandra Gangi, Mazen Noureddin, Ben A. Falk, Sungjin Kim, Wei Fan, Mourad Tighiouart, Sungyong You, Michael S. Lewis, Stephen J. Pandol, Dolores Di VizioAkil Merchant, Edwin M. Posadas, Neil A. Bhowmick, Shelly C. Lu, Ekihiro Seki

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

41 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1209-1226.e13
Journal	Cell Metabolism
Volume	35
Issue number	7
DOIs	https://doi.org/10.1016/j.cmet.2023.04.013
State	Published - Jul 11 2023

Keywords

colon cancer
CYR61
exosome
high-fat diet
liver metastasis
M2 macrophage
microRNA
non-alcoholic fatty liver disease
palmitate
Rab27a
Humans
Tumor Microenvironment
Extracellular Vesicles/metabolism
Fatty Liver/metabolism
Colorectal Neoplasms/metabolism
Protein Serine-Threonine Kinases/metabolism
Tumor Suppressor Proteins/metabolism
MicroRNAs/metabolism
Liver Neoplasms/metabolism

ASJC Scopus subject areas

Molecular Biology
Physiology
Cell Biology

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10.1016/j.cmet.2023.04.013

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Wang, Z., Kim, S. Y., Tu, W., Kim, J., Xu, A., Yang, Y. M., Matsuda, M., Reolizo, L., Tsuchiya, T., Billet, S., Gangi, A., Noureddin, M., Falk, B. A., Kim, S., Fan, W., Tighiouart, M., You, S., Lewis, M. S., Pandol, S. J., ... Seki, E. (2023). Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment. Cell Metabolism, 35(7), 1209-1226.e13. https://doi.org/10.1016/j.cmet.2023.04.013

Wang, Z, Kim, SY, Tu, W, Kim, J, Xu, A, Yang, YM, Matsuda, M, Reolizo, L, Tsuchiya, T, Billet, S, Gangi, A, Noureddin, M, Falk, BA, Kim, S, Fan, W, Tighiouart, M, You, S, Lewis, MS, Pandol, SJ, Di Vizio, D, Merchant, A, Posadas, EM, Bhowmick, NA, Lu, SC & Seki, E 2023, 'Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment', Cell Metabolism, vol. 35, no. 7, pp. 1209-1226.e13. https://doi.org/10.1016/j.cmet.2023.04.013

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title = "Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment",

abstract = "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.",

keywords = "colon cancer, CYR61, exosome, high-fat diet, liver metastasis, M2 macrophage, microRNA, non-alcoholic fatty liver disease, palmitate, Rab27a, Humans, Tumor Microenvironment, Extracellular Vesicles/metabolism, Fatty Liver/metabolism, Colorectal Neoplasms/metabolism, Protein Serine-Threonine Kinases/metabolism, Tumor Suppressor Proteins/metabolism, MicroRNAs/metabolism, Liver Neoplasms/metabolism",

author = "Zhijun Wang and Kim, {So Yeon} and Wei Tu and Jieun Kim and Alexander Xu and Yang, {Yoon Mee} and Michitaka Matsuda and Lien Reolizo and Takashi Tsuchiya and Sandrine Billet and Alexandra Gangi and Mazen Noureddin and Falk, {Ben A.} and Sungjin Kim and Wei Fan and Mourad Tighiouart and Sungyong You and Lewis, {Michael S.} and Pandol, {Stephen J.} and {Di Vizio}, Dolores and Akil Merchant and Posadas, {Edwin M.} and Bhowmick, {Neil A.} and Lu, {Shelly C.} and Ekihiro Seki",

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = jul,

day = "11",

doi = "10.1016/j.cmet.2023.04.013",

language = "English (US)",

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TY - JOUR

T1 - Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment

AU - Wang, Zhijun

AU - Kim, So Yeon

AU - Tu, Wei

AU - Kim, Jieun

AU - Xu, Alexander

AU - Yang, Yoon Mee

AU - Matsuda, Michitaka

AU - Reolizo, Lien

AU - Tsuchiya, Takashi

AU - Billet, Sandrine

AU - Gangi, Alexandra

AU - Noureddin, Mazen

AU - Falk, Ben A.

AU - Kim, Sungjin

AU - Fan, Wei

AU - Tighiouart, Mourad

AU - You, Sungyong

AU - Lewis, Michael S.

AU - Pandol, Stephen J.

AU - Di Vizio, Dolores

AU - Merchant, Akil

AU - Posadas, Edwin M.

AU - Bhowmick, Neil A.

AU - Lu, Shelly C.

AU - Seki, Ekihiro

PY - 2023/7/11

Y1 - 2023/7/11

N2 - 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.

AB - 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.

KW - colon cancer

KW - CYR61

KW - exosome

KW - high-fat diet

KW - liver metastasis

KW - M2 macrophage

KW - microRNA

KW - non-alcoholic fatty liver disease

KW - palmitate

KW - Rab27a

KW - Humans

KW - Tumor Microenvironment

KW - Extracellular Vesicles/metabolism

KW - Fatty Liver/metabolism

KW - Colorectal Neoplasms/metabolism

KW - Protein Serine-Threonine Kinases/metabolism

KW - Tumor Suppressor Proteins/metabolism

KW - MicroRNAs/metabolism

KW - Liver Neoplasms/metabolism

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U2 - 10.1016/j.cmet.2023.04.013

DO - 10.1016/j.cmet.2023.04.013

M3 - Article

C2 - 37172577

AN - SCOPUS:85160820609

SN - 1550-4131

VL - 35

SP - 1209-1226.e13

JO - Cell Metabolism

JF - Cell Metabolism

IS - 7

ER -

Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment

Abstract

Keywords

ASJC Scopus subject areas

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