SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer

• 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
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2017.63

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.