title: SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer.
abstract: Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of ~8%, restricted treatment options and characteristic molecular heterogeneity. SerpinB2 expression, particularly in the stromal compartment, is associated with reduced metastasis and prolonged survival in pancreatic ductal adenocarcinoma (PDAC) and our genomic analysis revealed that SERPINB2 is frequently deleted in PDAC. We show that SerpinB2 is required by stromal cells for normal collagen remodelling in vitro, regulating fibroblast interaction and engagement with collagen in the contracting matrix. In a pancreatic cancer allograft model, co-injection of PDAC cancer cells and SerpinB2-/-mouse embryonic fibroblasts (MEFs) resulted in increased tumour growth, aberrant remodelling of the extracellular matrix (ECM) and increased local invasion from the primary tumour. These tumours also displayed elevated proteolytic activity of the primary biochemical target of SerpinB2-urokinase plasminogen activator (uPA). In a large cohort of patients with resected PDAC, we show that increasing uPA mRNA expression was significantly associated with poorer survival following pancreatectomy. This study establishes a novel role for SerpinB2 in the stromal compartment in PDAC invasion through regulation of stromal remodelling and highlights the SerpinB2/uPA axis for further investigation as a potential therapeutic target in pancreatic cancer.
authors.affiliation: Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia.|Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, Australia.|School of Biological Sciences, University of Wollongong, Wollongong, Australia.
authors.forename: N L E
authors.initials: NLE
authors.lastname: Harris
authors.affiliation: Kinghorn Cancer Center, Garvan Institute of Medical Research, Darlinghurst, Australia.|St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Vennin
authors.affiliation: Kinghorn Cancer Center, Garvan Institute of Medical Research, Darlinghurst, Australia.|St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, Australia.
authors.forename: J R W
authors.initials: JRW
authors.lastname: Conway
authors.affiliation: Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia.|Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, Australia.|School of Biological Sciences, University of Wollongong, Wollongong, Australia.
authors.forename: K L
authors.initials: KL
authors.lastname: Vine
authors.affiliation: Kinghorn Cancer Center, Garvan Institute of Medical Research, Darlinghurst, Australia.
authors.forename: M
authors.identifier: 0000-0001-5078-6687
authors.initials: M
authors.lastname: Pinese
authors.affiliation: Kinghorn Cancer Center, Garvan Institute of Medical Research, Darlinghurst, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Cowley
authors.affiliation: Kinghorn Cancer Center, Garvan Institute of Medical Research, Darlinghurst, Australia.|St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, Australia.
authors.forename: R F
authors.initials: RF
authors.lastname: Shearer
authors.affiliation: Kinghorn Cancer Center, Garvan Institute of Medical Research, Darlinghurst, Australia.|St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, Australia.
authors.forename: M C
authors.initials: MC
authors.lastname: Lucas
authors.affiliation: Kinghorn Cancer Center, Garvan Institute of Medical Research, Darlinghurst, Australia.|St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Herrmann
authors.affiliation: Kinghorn Cancer Center, Garvan Institute of Medical Research, Darlinghurst, Australia.
authors.forename: A H
authors.initials: AH
authors.lastname: Allam
authors.affiliation: Kinghorn Cancer Center, Garvan Institute of Medical Research, Darlinghurst, Australia.|St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Pajic
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, Scotland.
authors.forename: J P
authors.initials: JP
authors.lastname: Morton
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: A V
authors.initials: AV
authors.lastname: Biankin
authors.affiliation: Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia.|Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, Australia.|School of Biological Sciences, University of Wollongong, Wollongong, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Ranson
authors.affiliation: Kinghorn Cancer Center, Garvan Institute of Medical Research, Darlinghurst, Australia.|St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Timpson
authors.affiliation: Kinghorn Cancer Center, Garvan Institute of Medical Research, Darlinghurst, Australia.|School of Medical Sciences, University of New South Wales, Sydney, Australia.
authors.forename: D N
authors.initials: DN
authors.lastname: Saunders
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008855:Microscopy, Electron, Scanning; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D017396:Plasminogen Activator Inhibitor 2 / Q000378:metabolism*; D059467:Transcriptome; D059016:Tumor Microenvironment
chemical_list: D017396:Plasminogen Activator Inhibitor 2