SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer

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 pancreati...

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Bibliographic Details
Published in:	Oncogene Vol. 36; no. 30; pp. 4288 - 4298
Main Authors:	Harris, N L E, Vennin, C, Conway, J R W, Vine, K L, Pinese, M, Cowley, M J, Shearer, R F, Lucas, M C, Herrmann, D, Allam, A H, Pajic, M, Morton, J P, Biankin, A V, Ranson, M, Timpson, P, Saunders, D N
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 27-07-2017 Nature Publishing Group
Subjects:	14/19 14/69 59 631/45/474 631/67/1504/1713 631/67/327 631/80/304 64/60 Adenocarcinoma Animals Apoptosis Carcinoma, Pancreatic Ductal - metabolism Carcinoma, Pancreatic Ductal - pathology Care and treatment Cell Biology Collagen Dosage and administration Embryo fibroblasts Embryos Extracellular matrix Fibroblasts - metabolism Fibroblasts - pathology Gemcitabine Gene expression Gene Expression Profiling Genomic analysis Human Genetics Humans Internal Medicine Medical prognosis Medicine Medicine & Public Health Metastases Mice Microscopy, Electron, Scanning Oncology Original original-article Pancreatectomy Pancreatic cancer Pancreatic islet transplantation Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Plasminogen Activator Inhibitor 2 - metabolism Proteolysis Rodents Scanning microscopy Stromal cells Survival Transcriptome Tumor Microenvironment Tumors U-Plasminogen activator
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work.
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2017.63