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Nat Cell Biol. 2016 May;18(5):549-60. doi: 10.1038/ncb3340. Epub 2016 Apr 18.

Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis.

Author information

1
Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
2
Department of Molecular and Clinical Pharmacology, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
3
Aging Intervention Research Center, KRIBB, 125 Gwahak-ro, Yuseong-gu, Deajeon 305-806, Korea.
4
Korea University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 305-350, Korea.
5
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
6
Lustgarten Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York 11724, USA.
7
Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
8
Department of Molecular Biotechnology and Health Sciences, Center for Molecular Biotechnology, University of Torino, Via Nizza 52, 10126 Turin, Italy.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating metastatic disease for which better therapies are urgently needed. Macrophages enhance metastasis in many cancer types; however, the role of macrophages in PDAC liver metastasis remains poorly understood. Here we found that PDAC liver metastasis critically depends on the early recruitment of granulin-secreting inflammatory monocytes to the liver. Mechanistically, we demonstrate that granulin secretion by metastasis-associated macrophages (MAMs) activates resident hepatic stellate cells (hStCs) into myofibroblasts that secrete periostin, resulting in a fibrotic microenvironment that sustains metastatic tumour growth. Disruption of MAM recruitment or genetic depletion of granulin reduced hStC activation and liver metastasis. Interestingly, we found that circulating monocytes and hepatic MAMs in PDAC patients express high levels of granulin. These findings suggest that recruitment of granulin-expressing inflammatory monocytes plays a key role in PDAC metastasis and may serve as a potential therapeutic target for PDAC liver metastasis.

PMID:
27088855
PMCID:
PMC4894551
DOI:
10.1038/ncb3340
[Indexed for MEDLINE]
Free PMC Article

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