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. (April 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)
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 Cancer Center Program > Signal Transduction CSHL labs > Tuveson lab CSHL Cancer Center Program > Cellular Communication in Cancer Program |
| Depositing User: | Matt Covey |
| Date: | 18 April 2016 |
| Date Deposited: | 26 Apr 2016 18:46 |
| Last Modified: | 26 Oct 2020 13:40 |
| PMCID: | PMC4894551 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/32626 |
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