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Cathepsin B promotes the progression of pancreatic ductal adenocarcinoma in mice
  1. Aarthi Gopinathan1,2,
  2. Gina M DeNicola1,2,
  3. Kristopher K Frese1,
  4. Natalie Cook1,
  5. Florian A Karreth1,
  6. Julia Mayerle3,
  7. Markus M Lerch3,
  8. Thomas Reinheckel4,5,
  9. David A Tuveson1
  1. 1Li Ka Shing Centre, Cancer Research UK Cambridge Research Institute, Cambridge, UK
  2. 2Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  3. 3Department of Medicine A, Ernst-Moritz-Arndt-Universitat Greifswald, Greifswald, Germany
  4. 4Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany
  5. 5BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany
  1. Correspondence to Dr David A Tuveson, Li Ka Shing Centre, Cancer Research UK Cambridge Research Institute, Robinson Way, Cambridge CB2 0RE, UK; david.tuveson{at}cancer.org.uk

Abstract

Objective The lysosomal protease cathepsin B is upregulated in human pancreatic ductal adenocarcinoma (PDA) and represents a potential therapeutic target. Loss of cathepsin B delays tumour progression in mouse models of islet, mammary and intestinal carcinoma and decreases invasion and metastasis. This study examines the role of cathepsin B in the initiation, progression and metastasis of PDA.

Methods Cathepsin B germline knockout mice were crossed with animals expressing an endogenous KrasG12D allele in the pancreas, and mice were aged to evaluate the role of cathepsin B in pancreatic intraepithelial neoplasia (PanIN). A survival study was also performed with mice carrying an additional heterozygous conditional Trp53R172H allele. Cell lines derived from tumours were used to investigate the role of cathepsin B in vitro, and subcutaneous allografts investigated the cell autonomous and non-cell autonomous roles of cathepsin B in pancreatic cancer.

Results Constitutive cathepsin B loss resulted in delayed progression of both PanIN and PDA and a significant survival advantage in mice. Cathepsin B-deficient PDA cells and PanIN showed decreased proliferation and mitogen-activated protein (MAP) kinase signalling. The reconstitution of deficient cells with cathepsin B reversed these findings, which correlated with decreased levels of the active forms of the related protease cathepsin L. Conversely, acute ablation of cathepsin L activated the MAP kinase cascade in PDA cells.

Conclusions These results confirm that cathepsin B plays an important cell autonomous role in the progression of PDA and suggest that the regulation of cathepsin L by cathepsin B may be a means of stimulating cell proliferation in neoplasia.

  • Cathepsin B
  • cathepsin L
  • pancreatic ductal adenocarcinoma
  • metastasis
  • Erk, cancer
  • cadherins
  • acini
  • epithelial cell adhesion
  • acute pancreatitis
  • adhesion molecules
  • pancreatic enzymes
  • pancreatitis
  • acute pancreatitis
  • pancreatic disorders
  • chronic pancreatitis

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Footnotes

  • Funding This work was supported by the Lustgarten Foundation, the University of Cambridge and Cancer Research UK, the Li Ka Shing Foundation and Hutchison Whampoa Limited, the National Institute for Health Research Cambridge Biomedical Research Centre, NIH (grants CA101973, CA111294, CA084291 and CA105490 to DAT) and the European Commission Seventh Framework Programme (FP7 Health 2010 2.4.1-6, contract number 256974). JM and MML were supported by Deutsche Krebshilfe/Dr Mildred-Scheel-Stiftung (109102), the Deutsche Forschungsgemeinschaft MA 4115/1-2/3 and the European Union (EU-FP-7: EPC-TM and EU-FP7-REGPOT-2010-1). TR was supported by European Commission FP7 grant 201279 (Microenvimet), the Deutsche Forschungsgemeinschaft SFB 850 project B7 and by the Excellence Initiative of the German Federal and State Governments (EXC 294).

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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