Hepatocytes direct the formation of a pro-metastatic niche in the liver

Jae W. Lee; Meredith L. Stone; Paige M. Porrett; Stacy K. Thomas; Chad A. Komar; Joey H. Li; Devora Delman; Kathleen Graham; Whitney L. Gladney; Xia Hua; Taylor A. Black; Austin L. Chien; Krishna S. Majmundar; Jeffrey C. Thompson; Stephanie S. Yee; Mark H. O’Hara; Charu Aggarwal; Dong Xin; Abraham Shaked; Mingming Gao; Dexi Liu; Mitesh J. Borad; Ramesh K. Ramanathan; Erica L. Carpenter; Ailing Ji; Maria C. de Beer; Frederick C. de Beer; Nancy R. Webb; Gregory L. Beatty

doi:10.1038/s41586-019-1004-y

Hepatocytes direct the formation of a pro-metastatic niche in the liver

Jae W. Lee, Meredith L. Stone, Paige M. Porrett, Stacy K. Thomas, Chad A. Komar, Joey H. Li, Devora Delman, Kathleen Graham, Whitney L. Gladney, Xia Hua, Taylor A. Black, Austin L. Chien, Krishna S. Majmundar, Jeffrey C. Thompson, Stephanie S. Yee, Mark H. O’Hara, Charu Aggarwal, Dong Xin, Abraham Shaked, Mingming GaoDexi Liu, Mitesh J. Borad, Ramesh K. Ramanathan, Erica L. Carpenter, Ailing Ji, Maria C. de Beer, Frederick C. de Beer, Nancy R. Webb, Gregory L. Beatty

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

201 Scopus citations

Abstract

The liver is the most common site of metastatic disease¹. Although this metastatic tropism may reflect the mechanical trapping of circulating tumour cells, liver metastasis is also dependent, at least in part, on the formation of a ‘pro-metastatic’ niche that supports the spread of tumour cells to the liver^2,3. The mechanisms that direct the formation of this niche are poorly understood. Here we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver and, in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. During early pancreatic tumorigenesis in mice, hepatocytes show activation of signal transducer and activator of transcription 3 (STAT3) signalling and increased production of serum amyloid A1 and A2 (referred to collectively as SAA). Overexpression of SAA by hepatocytes also occurs in patients with pancreatic and colorectal cancers that have metastasized to the liver, and many patients with locally advanced and metastatic disease show increases in circulating SAA. Activation of STAT3 in hepatocytes and the subsequent production of SAA depend on the release of interleukin 6 (IL-6) into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6–STAT3–SAA signalling prevents the establishment of a pro-metastatic niche and inhibits liver metastasis. Our data identify an intercellular network underpinned by hepatocytes that forms the basis of a pro-metastatic niche in the liver, and identify new therapeutic targets.

Original language	English
Pages (from-to)	249-252
Number of pages	4
Journal	Nature
Volume	567
Issue number	7747
DOIs	https://doi.org/10.1038/s41586-019-1004-y
State	Published - Mar 14 2019

Bibliographical note

Funding Information:
Acknowledgements We thank members of the Zaret laboratory for assistance with isolation and culture of primary hepatocytes and members of the Genomics Facility (Wistar Institute) and the Molecular Pathology and Imaging Core (University of Pennsylvania) for technical support; E. J. Wherry, D. J. Powell, J. R. Conejo-Garcia, I. E. Brodsky, and E. L. Stone for discussions and advice; and the Mayo Clinic Arizona for provision of liver tissue sections collected from patients with pancreatic cancer. This work was supported by National Institutes of Health grants F30 CA196106 (J.W.L.), T32 HL007439 (J.W.L.), T32 CA009140 (M.L.S.), R01 CA197916 (G.L.B.), R01 HL134731 (N.R.W. and F.C.d.B.), the University of Pennsylvania Molecular Pathology and Imaging Core of the Center for Molecular Studies in Digestive and Liver Diseases grant P30 DK050306, the 2015 Pancreatic Cancer Action Network-AACR Career Development Award 15-20-25-BEAT supported by an anonymous foundation (G.L.B.), the 2017 Stand Up to Cancer (SU2C) Innovative Research Grant SU2C-AACR-IRG 13-17 (G.L.B.), a Research Support Grant from the University of Kentucky Office of the Vice President for Research (N.R.W.), the American Surgical Association Foundation Fellowship (P.M.P.), the University of Pennsylvania Pancreatic Cancer Research Center (E.L.C.), and the Abramson Cancer Center Translational Centers of Excellence (E.L.C.).

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41586-019-1004-y

Cite this

Lee, J. W., Stone, M. L., Porrett, P. M., Thomas, S. K., Komar, C. A., Li, J. H., Delman, D., Graham, K., Gladney, W. L., Hua, X., Black, T. A., Chien, A. L., Majmundar, K. S., Thompson, J. C., Yee, S. S., O’Hara, M. H., Aggarwal, C., Xin, D., Shaked, A., ... Beatty, G. L. (2019). Hepatocytes direct the formation of a pro-metastatic niche in the liver. Nature, 567(7747), 249-252. https://doi.org/10.1038/s41586-019-1004-y

@article{d467613cef5148ab835e4ef93b05b1d5,

title = "Hepatocytes direct the formation of a pro-metastatic niche in the liver",

abstract = "The liver is the most common site of metastatic disease1. Although this metastatic tropism may reflect the mechanical trapping of circulating tumour cells, liver metastasis is also dependent, at least in part, on the formation of a {\textquoteleft}pro-metastatic{\textquoteright} niche that supports the spread of tumour cells to the liver2,3. The mechanisms that direct the formation of this niche are poorly understood. Here we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver and, in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. During early pancreatic tumorigenesis in mice, hepatocytes show activation of signal transducer and activator of transcription 3 (STAT3) signalling and increased production of serum amyloid A1 and A2 (referred to collectively as SAA). Overexpression of SAA by hepatocytes also occurs in patients with pancreatic and colorectal cancers that have metastasized to the liver, and many patients with locally advanced and metastatic disease show increases in circulating SAA. Activation of STAT3 in hepatocytes and the subsequent production of SAA depend on the release of interleukin 6 (IL-6) into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6–STAT3–SAA signalling prevents the establishment of a pro-metastatic niche and inhibits liver metastasis. Our data identify an intercellular network underpinned by hepatocytes that forms the basis of a pro-metastatic niche in the liver, and identify new therapeutic targets.",

author = "Lee, {Jae W.} and Stone, {Meredith L.} and Porrett, {Paige M.} and Thomas, {Stacy K.} and Komar, {Chad A.} and Li, {Joey H.} and Devora Delman and Kathleen Graham and Gladney, {Whitney L.} and Xia Hua and Black, {Taylor A.} and Chien, {Austin L.} and Majmundar, {Krishna S.} and Thompson, {Jeffrey C.} and Yee, {Stephanie S.} and O{\textquoteright}Hara, {Mark H.} and Charu Aggarwal and Dong Xin and Abraham Shaked and Mingming Gao and Dexi Liu and Borad, {Mitesh J.} and Ramanathan, {Ramesh K.} and Carpenter, {Erica L.} and Ailing Ji and {de Beer}, {Maria C.} and {de Beer}, {Frederick C.} and Webb, {Nancy R.} and Beatty, {Gregory L.}",

note = "Funding Information: Acknowledgements We thank members of the Zaret laboratory for assistance with isolation and culture of primary hepatocytes and members of the Genomics Facility (Wistar Institute) and the Molecular Pathology and Imaging Core (University of Pennsylvania) for technical support; E. J. Wherry, D. J. Powell, J. R. Conejo-Garcia, I. E. Brodsky, and E. L. Stone for discussions and advice; and the Mayo Clinic Arizona for provision of liver tissue sections collected from patients with pancreatic cancer. This work was supported by National Institutes of Health grants F30 CA196106 (J.W.L.), T32 HL007439 (J.W.L.), T32 CA009140 (M.L.S.), R01 CA197916 (G.L.B.), R01 HL134731 (N.R.W. and F.C.d.B.), the University of Pennsylvania Molecular Pathology and Imaging Core of the Center for Molecular Studies in Digestive and Liver Diseases grant P30 DK050306, the 2015 Pancreatic Cancer Action Network-AACR Career Development Award 15-20-25-BEAT supported by an anonymous foundation (G.L.B.), the 2017 Stand Up to Cancer (SU2C) Innovative Research Grant SU2C-AACR-IRG 13-17 (G.L.B.), a Research Support Grant from the University of Kentucky Office of the Vice President for Research (N.R.W.), the American Surgical Association Foundation Fellowship (P.M.P.), the University of Pennsylvania Pancreatic Cancer Research Center (E.L.C.), and the Abramson Cancer Center Translational Centers of Excellence (E.L.C.). Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2019",

month = mar,

day = "14",

doi = "10.1038/s41586-019-1004-y",

language = "English",

volume = "567",

pages = "249--252",

number = "7747",

}

Lee, JW, Stone, ML, Porrett, PM, Thomas, SK, Komar, CA, Li, JH, Delman, D, Graham, K, Gladney, WL, Hua, X, Black, TA, Chien, AL, Majmundar, KS, Thompson, JC, Yee, SS, O’Hara, MH, Aggarwal, C, Xin, D, Shaked, A, Gao, M, Liu, D, Borad, MJ, Ramanathan, RK, Carpenter, EL, Ji, A, de Beer, MC, de Beer, FC, Webb, NR & Beatty, GL 2019, 'Hepatocytes direct the formation of a pro-metastatic niche in the liver', Nature, vol. 567, no. 7747, pp. 249-252. https://doi.org/10.1038/s41586-019-1004-y

TY - JOUR

T1 - Hepatocytes direct the formation of a pro-metastatic niche in the liver

AU - Lee, Jae W.

AU - Stone, Meredith L.

AU - Porrett, Paige M.

AU - Thomas, Stacy K.

AU - Komar, Chad A.

AU - Li, Joey H.

AU - Delman, Devora

AU - Graham, Kathleen

AU - Gladney, Whitney L.

AU - Hua, Xia

AU - Black, Taylor A.

AU - Chien, Austin L.

AU - Majmundar, Krishna S.

AU - Thompson, Jeffrey C.

AU - Yee, Stephanie S.

AU - O’Hara, Mark H.

AU - Aggarwal, Charu

AU - Xin, Dong

AU - Shaked, Abraham

AU - Gao, Mingming

AU - Liu, Dexi

AU - Borad, Mitesh J.

AU - Ramanathan, Ramesh K.

AU - Carpenter, Erica L.

AU - Ji, Ailing

AU - de Beer, Maria C.

AU - de Beer, Frederick C.

AU - Webb, Nancy R.

AU - Beatty, Gregory L.

N1 - Funding Information: Acknowledgements We thank members of the Zaret laboratory for assistance with isolation and culture of primary hepatocytes and members of the Genomics Facility (Wistar Institute) and the Molecular Pathology and Imaging Core (University of Pennsylvania) for technical support; E. J. Wherry, D. J. Powell, J. R. Conejo-Garcia, I. E. Brodsky, and E. L. Stone for discussions and advice; and the Mayo Clinic Arizona for provision of liver tissue sections collected from patients with pancreatic cancer. This work was supported by National Institutes of Health grants F30 CA196106 (J.W.L.), T32 HL007439 (J.W.L.), T32 CA009140 (M.L.S.), R01 CA197916 (G.L.B.), R01 HL134731 (N.R.W. and F.C.d.B.), the University of Pennsylvania Molecular Pathology and Imaging Core of the Center for Molecular Studies in Digestive and Liver Diseases grant P30 DK050306, the 2015 Pancreatic Cancer Action Network-AACR Career Development Award 15-20-25-BEAT supported by an anonymous foundation (G.L.B.), the 2017 Stand Up to Cancer (SU2C) Innovative Research Grant SU2C-AACR-IRG 13-17 (G.L.B.), a Research Support Grant from the University of Kentucky Office of the Vice President for Research (N.R.W.), the American Surgical Association Foundation Fellowship (P.M.P.), the University of Pennsylvania Pancreatic Cancer Research Center (E.L.C.), and the Abramson Cancer Center Translational Centers of Excellence (E.L.C.). Publisher Copyright: © 2019, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2019/3/14

Y1 - 2019/3/14

N2 - The liver is the most common site of metastatic disease1. Although this metastatic tropism may reflect the mechanical trapping of circulating tumour cells, liver metastasis is also dependent, at least in part, on the formation of a ‘pro-metastatic’ niche that supports the spread of tumour cells to the liver2,3. The mechanisms that direct the formation of this niche are poorly understood. Here we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver and, in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. During early pancreatic tumorigenesis in mice, hepatocytes show activation of signal transducer and activator of transcription 3 (STAT3) signalling and increased production of serum amyloid A1 and A2 (referred to collectively as SAA). Overexpression of SAA by hepatocytes also occurs in patients with pancreatic and colorectal cancers that have metastasized to the liver, and many patients with locally advanced and metastatic disease show increases in circulating SAA. Activation of STAT3 in hepatocytes and the subsequent production of SAA depend on the release of interleukin 6 (IL-6) into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6–STAT3–SAA signalling prevents the establishment of a pro-metastatic niche and inhibits liver metastasis. Our data identify an intercellular network underpinned by hepatocytes that forms the basis of a pro-metastatic niche in the liver, and identify new therapeutic targets.

AB - The liver is the most common site of metastatic disease1. Although this metastatic tropism may reflect the mechanical trapping of circulating tumour cells, liver metastasis is also dependent, at least in part, on the formation of a ‘pro-metastatic’ niche that supports the spread of tumour cells to the liver2,3. The mechanisms that direct the formation of this niche are poorly understood. Here we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver and, in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. During early pancreatic tumorigenesis in mice, hepatocytes show activation of signal transducer and activator of transcription 3 (STAT3) signalling and increased production of serum amyloid A1 and A2 (referred to collectively as SAA). Overexpression of SAA by hepatocytes also occurs in patients with pancreatic and colorectal cancers that have metastasized to the liver, and many patients with locally advanced and metastatic disease show increases in circulating SAA. Activation of STAT3 in hepatocytes and the subsequent production of SAA depend on the release of interleukin 6 (IL-6) into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6–STAT3–SAA signalling prevents the establishment of a pro-metastatic niche and inhibits liver metastasis. Our data identify an intercellular network underpinned by hepatocytes that forms the basis of a pro-metastatic niche in the liver, and identify new therapeutic targets.

UR - http://www.scopus.com/inward/record.url?scp=85062691344&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062691344&partnerID=8YFLogxK

U2 - 10.1038/s41586-019-1004-y

DO - 10.1038/s41586-019-1004-y

M3 - Article

C2 - 30842658

AN - SCOPUS:85062691344

SN - 0028-0836

VL - 567

SP - 249

EP - 252

JO - Nature

JF - Nature

IS - 7747

ER -

Hepatocytes direct the formation of a pro-metastatic niche in the liver

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this