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

Sebastian R. Nielsen, Valeria Quaranta, Andrea Linford, Perpetua Emeagi, Carolyn Rainer, Almudena Santos, Lucy Ireland, Takao Sakai, Keiko Sakai, Yong Sam Kim, Dannielle Engle, Fiona Campbell, Daniel Palmer, Jeong Heon Ko, David A. Tuveson, Emilio Hirsch, Ainhoa Mielgo, Michael C. Schmid

Research output: Contribution to journalArticlepeer-review

318 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)549-560
Number of pages12
JournalNature Cell Biology
Volume18
Issue number5
DOIs
Publication statusPublished - 01-05-2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cell Biology

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