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

• Published in: Nature cell biology Vol. 18; no. 5; pp. 549 - 560
• Main Authors: Nielsen, Sebastian R, Quaranta, Valeria, Linford, Andrea, Emeagi, Perpetua, Rainer, Carolyn, Santos, Almudena, Ireland, Lucy, Sakai, Takao, Sakai, Keiko, Kim, Yong-Sam, Engle, Dannielle, Campbell, Fiona, Palmer, Daniel, Ko, Jeong Heon, Tuveson, David A, Hirsch, Emilio, Mielgo, Ainhoa, Schmid, Michael C
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.05.2016
• Subjects: Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animals; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Cell Proliferation; Complications and side effects; Genetic aspects; Health aspects; Hepatic Stellate Cells - pathology; Humans; Inflammation - pathology; Intercellular Signaling Peptides and Proteins - metabolism; Liver cancer; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Macrophages - metabolism; Macrophages - pathology; Metastasis; Mice; Monocytes; Monocytes - metabolism; Monocytes - pathology; Myofibroblasts - metabolism; Myofibroblasts - pathology; Neoplasm Metastasis; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Progranulins; Risk factors
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb3340

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.