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 journalArticlepeer-review

201 Scopus citations


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.

Original languageEnglish
Pages (from-to)249-252
Number of pages4
Issue number7747
StatePublished - 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.

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