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. Beer, Frederick C. Beer, Nancy R. Webb and Gregory L. Beatty ()
Additional contact information
Jae W. Lee: University of Pennsylvania
Meredith L. Stone: University of Pennsylvania
Paige M. Porrett: Perelman School of Medicine, University of Pennsylvania
Stacy K. Thomas: University of Pennsylvania
Chad A. Komar: University of Pennsylvania
Joey H. Li: University of Pennsylvania
Devora Delman: University of Pennsylvania
Kathleen Graham: University of Pennsylvania
Whitney L. Gladney: University of Pennsylvania
Xia Hua: University of Pennsylvania
Taylor A. Black: University of Pennsylvania
Austin L. Chien: University of Pennsylvania
Krishna S. Majmundar: University of Pennsylvania
Jeffrey C. Thompson: University of Pennsylvania
Stephanie S. Yee: University of Pennsylvania
Mark H. O’Hara: University of Pennsylvania
Charu Aggarwal: University of Pennsylvania
Dong Xin: Perelman School of Medicine, University of Pennsylvania
Abraham Shaked: Perelman School of Medicine, University of Pennsylvania
Mingming Gao: College of Pharmacy, University of Georgia
Dexi Liu: College of Pharmacy, University of Georgia
Mitesh J. Borad: Mayo Clinic
Ramesh K. Ramanathan: Mayo Clinic
Erica L. Carpenter: University of Pennsylvania
Ailing Ji: University of Kentucky
Maria C. Beer: University of Kentucky
Frederick C. Beer: University of Kentucky
Nancy R. Webb: University of Kentucky
Gregory L. Beatty: University of Pennsylvania

Nature, 2019, vol. 567, issue 7747, 249-252

Abstract: 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 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.

Date: 2019
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DOI: 10.1038/s41586-019-1004-y

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