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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Additional file 6 of Unraveling temporal and spatial biomarkers of epithelial-mesenchymal transition in colorectal cancer: insights into the crucial role of immunosuppressive cells
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Additional file 12 of Unraveling temporal and spatial biomarkers of epithelial-mesenchymal transition in colorectal cancer: insights into the crucial role of immunosuppressive cells
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Additional file 11 of Unraveling temporal and spatial biomarkers of epithelial-mesenchymal transition in colorectal cancer: insights into the crucial role of immunosuppressive cells
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Additional file 2 of Unraveling temporal and spatial biomarkers of epithelial-mesenchymal transition in colorectal cancer: insights into the crucial role of immunosuppressive cells
Wang, M., Deng, C., Yang, C., Yan, M., Lu, H., Zhang, Y., Liu, H., Tong, Z., Ma, J., Wang, J., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26637363
Additional file 13 of Unraveling temporal and spatial biomarkers of epithelial-mesenchymal transition in colorectal cancer: insights into the crucial role of immunosuppressive cells
Wang, M., Deng, C., Yang, C., Yan, M., Lu, H., Zhang, Y., Liu, H., Tong, Z., Ma, J., Wang, J., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26637396
Additional file 4 of Colorectal cancer-derived small extracellular vesicles induce TGFβ1-mediated epithelial to mesenchymal transition of hepatocytes
Pucci, M., Moschetti, M., Urzì, O., Loria, M., Conigliaro, A., Bella, M. A. D., Crescitelli, R., Bagge, R. O., Gallo, A., Santos, M. F., et al. (2023) · Figshare · doi:10.6084/m9.figshare.26583195
Additional file 6 of Colorectal cancer-derived small extracellular vesicles induce TGFβ1-mediated epithelial to mesenchymal transition of hepatocytes
Pucci, M., Moschetti, M., Urzì, O., Loria, M., Conigliaro, A., Bella, M. A. D., Crescitelli, R., Bagge, R. O., Gallo, A., Santos, M. F., et al. (2023) · Figshare · doi:10.6084/m9.figshare.26583198
Additional file 2 of Gastric cancer-derived LBP promotes liver metastasis by driving intrahepatic fibrotic pre-metastatic niche formation
Xie, L., Qiu, S., Lu, C., Gu, C., Wang, J., Lv, J., Fang, L., Chen, Z., Li, Y., Jiang, T., et al. (2024) · Figshare · doi:10.6084/m9.figshare.24240218
Additional file 2 of Hepatocyte SGK1 activated by hepatic ischemia-reperfusion promotes the recurrence of liver metastasis via IL-6/STAT3
Li, X., Wang, Z., Jiao, C., Zhang, Y., Xia, N. L., Yu, W., Chen, X., Wikana, L. P., Liu, Y., Sun, L., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26568550
Additional file 1 of Unraveling temporal and spatial biomarkers of epithelial-mesenchymal transition in colorectal cancer: insights into the crucial role of immunosuppressive cells
Wang, M., Deng, C., Yang, C., Yan, M., Lu, H., Zhang, Y., Liu, H., Tong, Z., Ma, J., Wang, J., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26637360
Additional file 16 of Unraveling temporal and spatial biomarkers of epithelial-mesenchymal transition in colorectal cancer: insights into the crucial role of immunosuppressive cells
Wang, M., Deng, C., Yang, C., Yan, M., Lu, H., Zhang, Y., Liu, H., Tong, Z., Ma, J., Wang, J., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26637405
Additional file 1 of Do malignant cells sleep at night?
Cortés‐Hernández, L. E., Eslami‐S, Z., Dujon, A. M., Giraudeau, M., Újvári, B., Frédéric Thomas, A., & Alix‐Panabières, C. (2020) · Figshare · doi:10.6084/m9.figshare.13232994
Additional file 8 of Unraveling temporal and spatial biomarkers of epithelial-mesenchymal transition in colorectal cancer: insights into the crucial role of immunosuppressive cells
Wang, M., Deng, C., Yang, C., Yan, M., Lu, H., Zhang, Y., Liu, H., Tong, Z., Ma, J., Wang, J., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26637381
Additional file 10 of Unraveling temporal and spatial biomarkers of epithelial-mesenchymal transition in colorectal cancer: insights into the crucial role of immunosuppressive cells
Wang, M., Deng, C., Yang, C., Yan, M., Lu, H., Zhang, Y., Liu, H., Tong, Z., Ma, J., Wang, J., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26637387
Additional file 3 of Unraveling temporal and spatial biomarkers of epithelial-mesenchymal transition in colorectal cancer: insights into the crucial role of immunosuppressive cells
Wang, M., Deng, C., Yang, C., Yan, M., Lu, H., Zhang, Y., Liu, H., Tong, Z., Ma, J., Wang, J., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26637366
Additional file 1 of Feline mammary carcinoma-derived extracellular vesicle promotes liver metastasis via sphingosine kinase-1-mediated premetastatic niche formation
Chang, Y.-C., Liu, H.-P., Chuang, H.-L., Liao, J.-W., Kao, P.-L., Chan, H.-L., Chen, T.-H., & Wang, Y.-C. (2023) · Figshare · doi:10.6084/m9.figshare.24531975
Additional file 7 of Unraveling temporal and spatial biomarkers of epithelial-mesenchymal transition in colorectal cancer: insights into the crucial role of immunosuppressive cells
Wang, M., Deng, C., Yang, C., Yan, M., Lu, H., Zhang, Y., Liu, H., Tong, Z., Ma, J., Wang, J., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26637378
Additional file 5 of Unraveling temporal and spatial biomarkers of epithelial-mesenchymal transition in colorectal cancer: insights into the crucial role of immunosuppressive cells
Wang, M., Deng, C., Yang, C., Yan, M., Lu, H., Zhang, Y., Liu, H., Tong, Z., Ma, J., Wang, J., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26637372
Additional file 8 of Colorectal cancer-derived small extracellular vesicles induce TGFβ1-mediated epithelial to mesenchymal transition of hepatocytes
Pucci, M., Moschetti, M., Urzì, O., Loria, M., Conigliaro, A., Bella, M. A. D., Crescitelli, R., Bagge, R. O., Gallo, A., Santos, M. F., et al. (2023) · Figshare · doi:10.6084/m9.figshare.26583204
Additional file 14 of Unraveling temporal and spatial biomarkers of epithelial-mesenchymal transition in colorectal cancer: insights into the crucial role of immunosuppressive cells
Wang, M., Deng, C., Yang, C., Yan, M., Lu, H., Zhang, Y., Liu, H., Tong, Z., Ma, J., Wang, J., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26637399
Additional file 1 of Hepatocyte SGK1 activated by hepatic ischemia-reperfusion promotes the recurrence of liver metastasis via IL-6/STAT3
Li, X., Wang, Z., Jiao, C., Zhang, Y., Xia, N., Yu, W., Chen, X., Wikana, L. P., Liu, Y., Sun, L., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26568547
Additional file 7 of Colorectal cancer-derived small extracellular vesicles induce TGFβ1-mediated epithelial to mesenchymal transition of hepatocytes
Pucci, M., Moschetti, M., Urzì, O., Loria, M., Conigliaro, A., Bella, M. A. D., Crescitelli, R., Bagge, R. O., Gallo, A., Santos, M. F., et al. (2023) · Figshare · doi:10.6084/m9.figshare.26583201
Additional file 9 of Unraveling temporal and spatial biomarkers of epithelial-mesenchymal transition in colorectal cancer: insights into the crucial role of immunosuppressive cells
Wang, M., Deng, C., Yang, C., Yan, M., Lu, H., Zhang, Y., Liu, H., Tong, Z., Ma, J., Wang, J., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26637384
Additional file 3 of Colorectal cancer-derived small extracellular vesicles induce TGFβ1-mediated epithelial to mesenchymal transition of hepatocytes
Pucci, M., Moschetti, M., Urzì, O., Loria, M., Conigliaro, A., Bella, M. A. D., Crescitelli, R., Bagge, R. O., Gallo, A., Santos, M. F., et al. (2023) · Figshare · doi:10.6084/m9.figshare.26583192
Additional file 15 of Unraveling temporal and spatial biomarkers of epithelial-mesenchymal transition in colorectal cancer: insights into the crucial role of immunosuppressive cells
Wang, M., Deng, C., Yang, C., Yan, M., Lu, H., Zhang, Y., Liu, H., Tong, Z., Ma, J., Wang, J., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26637402
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Hue, J. J., Zarei, M., Sunita, P., Abul-Khoudoud, S. O., Dey, G., Graor, H. J., Blise, K. E., Keith, D., Sivagnanam, S., Pattanayak, S. P., et al. (2026) · Cancer Research Communications · doi:10.1158/2767-9764.crc-25-0338

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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