Cited by 410Cytokine Signaling Pathways and InteractionsCancer Cells and MetastasisImmune cells in cancer

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

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Lee, Jae W., Stone, Meredith L., Porrett, Paige M., Thomas, Stacy K., Komar, Chad A., Li, Joey H., Delman, Devora, Graham, Kathleen, Gladney, Whitney L., Hua, Xia, Black, Taylor A., Chien, Austin L., Majmundar, Krishna S., Thompson, Jeffrey C., Yee, Stephanie S., O’Hara, Mark H., Aggarwal, Charu, Xin, Dong, Shaked, Abraham, Gao, Mingming, Liu, Dexi, Borad, Mitesh J., Ramanathan, Ramesh K., Carpenter, Erica L., Ji, Ailing, de Beer, Maria C., de Beer, Frederick C., Webb, Nancy R., Beatty, Gregory L.·2019·Nature

DOI 10.1038/s41586-019-1004-yPMC PMC6430113

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Abstract

The liver is the most common site of metastatic disease 1. 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.

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Authors: 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., Gao, M., Liu, D., Borad, M. J., Ramanathan, R. K., Carpenter, E. L., Ji, A., de Beer, M. C., de Beer, F. C., Webb, N. R., & Beatty, G. L.
Affiliations: Abramson Cancer Center (US)
University of Pennsylvania (US)
University of Georgia (US)
Mayo Clinic Comprehensive Cancer Center (Arizona) (US)
Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
University of Kentucky (US)
Corresponding author: Beatty, Gregory L.
ORCID: Lee, Jae W.
Stone, Meredith L.
Porrett, Paige M.
Thomas, Stacy K.
Li, Joey H.
Graham, Kathleen
Gladney, Whitney L.
Chien, Austin L.
Thompson, Jeffrey C.
Yee, Stephanie S.
O’Hara, Mark H.
Aggarwal, Charu
Xin, Dong
Shaked, Abraham
Gao, Mingming
Liu, Dexi
Borad, Mitesh J.
Carpenter, Erica L.
Ji, Ailing
de Beer, Maria C.
de Beer, Frederick C.
Webb, Nancy R.
Beatty, Gregory L.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2019-03-06
Volume: 567
Issue: 7747
Pages: 249-252
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-019-1004-y
PMC: PMC6430113
OpenAlex: W2919508314
Cited by: 402
References: 41
Citations by year: 2026: 30 · 2025: 55 · 2024: 55 · 2023: 64 · 2022: 54 · 2021: 58 · 2020: 57 · 2019: 26
FWCI: 20.38
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: University of Pennsylvania
National Heart, Lung, and Blood Institute (R01HL134731, T32HL007439)
National Cancer Institute (T32CA009140, F30CA196106, R01CA197916, P30CA016520)
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK050306)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords: liver metastasis, hepatocytes, STAT3 signaling, serum amyloid A, interleukin-6, pancreatic cancer, colorectal cancer, liver fibrosis, tumor microenvironment, metastatic tropism
MeSH terms: Serum Amyloid A Protein, Animals, Female, Liver, Liver Neoplasms, Male, Neoplasm Metastasis, Pancreatic Neoplasms, Colorectal Neoplasms, Interleukin-6, Carcinoma, Pancreatic Ductal, Hepatocytes, STAT3 Transcription Factor, Mice, Tumor Microenvironment

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

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