Journal
ONCOGENE
Volume 36, Issue 30, Pages 4288-4298Publisher
SPRINGERNATURE
DOI: 10.1038/onc.2017.63
Keywords
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Funding
- National Health and Medical Research Council
- Cancer Institute NSW
- Cancer Council NSW
- Tour De Cure
- Cure Cancer Australia Foundation
- Australian Research Council
- University of Wollongong
- Illawarra Health and Medical Research Institute
- Mostyn Family Foundation
- Garvan Research Foundation
- Sydney Catalyst
- Lens Ainsworth Pancreatic Cancer Fellowship
- University of Wollongong Vice Chancellor's Fellowship
- Australian Postgraduate Award PhD scholarship
- Guest Family Fellowship
- Cancer Research UK [22311] Funding Source: researchfish
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Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of similar to 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.
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