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

Nielsen, S. R., Quaranta, V., Linford, A., Emeagi, P., Rainer, C., Santos, A., Ireland, L., Sakai, T., Sakai, K., Kim, Y. S., Engle, D., Campbell, F., Palmer, D., Ko, J. H., Tuveson, D. A., Hirsch, E., Mielgo, A., Schmid, M. C. (2016) Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. Nat Cell Biol, 18 (5). pp. 549-60. ISSN 1476-4679 (Electronic)1465-7392 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/27088855
DOI: 10.1038/ncb3340

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.

Item Type: Paper
Subjects: diseases & disorders > cancer
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > macrophages
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > macrophages
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > macrophages

diseases & disorders > cancer > metastasis
diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:
Communities: CSHL labs > Tuveson lab
Depositing User: Matt Covey
Date Deposited: 26 Apr 2016 18:46
Last Modified: 05 Jun 2017 16:48
PMCID: PMC4894551
Related URLs:
URI: http://repository.cshl.edu/id/eprint/32626

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