title: Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis.
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.
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
authors.forename: Sebastian R
authors.initials: SR
authors.lastname: Nielsen
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
authors.forename: Valeria
authors.initials: V
authors.lastname: Quaranta
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Linford
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
authors.forename: Perpetua
authors.initials: P
authors.lastname: Emeagi
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Rainer
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
authors.forename: Almudena
authors.initials: A
authors.lastname: Santos
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Ireland
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
authors.forename: Takao
authors.initials: T
authors.lastname: Sakai
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
authors.forename: Keiko
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Aging Intervention Research Center, KRIBB, 125 Gwahak-ro, Yuseong-gu, Deajeon 305-806, Korea.|Korea University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 305-350, Korea.
authors.forename: Yong-Sam
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.|Lustgarten Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Dannielle
authors.identifier: 0000-0003-1876-7675
authors.initials: D
authors.lastname: Engle
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Campbell
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Palmer
authors.affiliation: Aging Intervention Research Center, KRIBB, 125 Gwahak-ro, Yuseong-gu, Deajeon 305-806, Korea.|Korea University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 305-350, Korea.
authors.forename: Jeong Heon
authors.initials: JH
authors.lastname: Ko
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.|Lustgarten Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York 11724, USA.|Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Center for Molecular Biotechnology, University of Torino, Via Nizza 52, 10126 Turin, Italy.
authors.forename: Emilio
authors.identifier: 0000-0002-9073-6024
authors.initials: E
authors.lastname: Hirsch
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Mielgo
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Schmid
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055166:Hepatic Stellate Cells / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000077153:Progranulins
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins