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

Y. Su, J. Li, A. K. Witkiewicz, D. Brennan, T. Neill, J. Talarico, G. L. Radice

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 Kras G12D and mutant p53 (Trp53 R172H) 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, P0.05) 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.

Original languageEnglish (US)
Pages (from-to)4484-4489
Number of pages6
JournalOncogene
Volume31
Issue number41
DOIs
StatePublished - Oct 11 2012

Fingerprint

Haploinsufficiency
Cadherins
Pancreatic Neoplasms
Adenocarcinoma
Survival
Neoplasms
Matrix Metalloproteinase 7
Hedgehogs
Matrix Metalloproteinases
Cell Adhesion
Disease Progression
Pancreas
Cell Survival
Membrane Proteins
Carcinogenesis
Up-Regulation
Animal Models
Alleles
Therapeutics

Keywords

  • apoptosis
  • cell adhesion
  • invasion
  • matrix metalloproteinase

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Su, Y., Li, J., Witkiewicz, A. K., Brennan, D., Neill, T., Talarico, J., & Radice, G. L. (2012). N-cadherin haploinsufficiency increases survival in a mouse model of pancreatic cancer. Oncogene, 31(41), 4484-4489. https://doi.org/10.1038/onc.2011.574

N-cadherin haploinsufficiency increases survival in a mouse model of pancreatic cancer. / Su, Y.; Li, J.; Witkiewicz, A. K.; Brennan, D.; Neill, T.; Talarico, J.; Radice, G. L.

In: Oncogene, Vol. 31, No. 41, 11.10.2012, p. 4484-4489.

Research output: Contribution to journalArticle

Su, Y, Li, J, Witkiewicz, AK, Brennan, D, Neill, T, Talarico, J & Radice, GL 2012, 'N-cadherin haploinsufficiency increases survival in a mouse model of pancreatic cancer', Oncogene, vol. 31, no. 41, pp. 4484-4489. https://doi.org/10.1038/onc.2011.574
Su, Y. ; Li, J. ; Witkiewicz, A. K. ; Brennan, D. ; Neill, T. ; Talarico, J. ; Radice, G. L. / N-cadherin haploinsufficiency increases survival in a mouse model of pancreatic cancer. In: Oncogene. 2012 ; Vol. 31, No. 41. pp. 4484-4489.
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