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N-cadherin haploinsufficiency increases survival in a mouse model of pancreatic cancer

Oncogene volume 31, pages 4484–4489 (2012)Cite this article

Abstract

Pancreatic ductal adenocarcinoma (PDA) is often detected at a late stage, hence the identification of new therapies that have potential to block tumor progression is critical for this lethal disease. N-cadherin upregulation has been observed in many cancers including PDA, however, a causal role for this cell adhesion receptor in disease progression has yet to be defined. The concomitant expression of oncogenic KrasG12D and mutant p53 (Trp53R172H) in the murine pancreas results in metastatic PDA that recapitulates the cognate features of human pancreatic cancer providing an excellent animal model to identify genes required for tumor progression. Here we determine the consequences of genetically manipulating N-cadherin expression in a mouse model of PDA. Remarkably, mice with reduced N-cadherin expression (that is, Ncad−/+) survived 25% longer (177 vs 142 days, P<0.05) than animals expressing two wild-type N-cadherin (Cdh2) alleles. The survival benefit is likely due to a cumulative effect of N-cadherin's role in different aspects of tumorigenesis including tumor-cell survival, growth, migration and invasion. Interestingly, reduced hedgehog signaling may contribute to the better prognosis for the Ncad−/+ mice. Moreover, the matrix metalloproteinase MMP-7, associated with poor prognosis in PDA, was reduced in Ncad−/+ tumors. Finally, Ncad−/+ tumor cells exhibited decreased FGF-stimulated ERK1/2 activation consistent with N-cadherin's ability to promote FGFR signaling. These data support a critical role for N-cadherin in PDA and its potential prognostic value. Additionally, this study provides in vivo genetic evidence that the cell-surface protein N-cadherin represents a promising therapeutic target for the treatment of pancreatic cancer.

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Acknowledgements

We thank Dr D Tuveson (Cancer Research UK, Cambridge) for the LSL-K-rasG12D and LSL-Trp53R172H mice and Dr A Lowy (UCSD) for the Pdx1/Cre mice. We are grateful to Han Du, Craig Riley, David Kurz, Leeanne Griffith and Andrew Ho for technical assistance. This work was supported by the Center for Molecular Studies in Digestive and Liver Disease (NIH P30DK050306) and University Research Foundation—University of Pennsylvania, NIH R21 CA133609, Pilot Research Award—Thomas Jefferson University (to GLR).

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Authors and Affiliations

  1. Department of Medicine, Center for Translational Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA

    Y Su, J Li, D Brennan, T Neill, J Talarico & G L Radice

  2. Department of Pathology, Anatomy, and Cell Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    A K Witkiewicz

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  1. Y Su
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Correspondence to G L Radice.

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Su, Y., Li, J., Witkiewicz, A. et al. N-cadherin haploinsufficiency increases survival in a mouse model of pancreatic cancer. Oncogene 31, 4484–4489 (2012). https://doi.org/10.1038/onc.2011.574

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