Stabilization of β-Catenin Induces Pancreas Tumor Formation

Patrick W. Heiser, David A. Cano, Limor Landsman, Grace E. Kim, James G. Kench, David S. Klimstra, Maketo M. Taketo, Andrew V. Biankin, Matthias Hebrok*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

135 Scopus citations


Background & Aims: β-Catenin signaling within the canonical Wnt pathway is essential for pancreas development. However, the pathway is normally down-regulated in the adult organ. Increased cytoplasmic and nuclear localization of β-catenin can be detected in nearly all human solid pseudopapillary neoplasms (SPN), a rare tumor with low malignant potential. Conversely, pancreatic ductal adenocarcinoma (PDA) accounts for the majority of pancreatic tumors and is among the leading causes of cancer death. Whereas activating mutations within β-catenin and other members of the canonical Wnt pathway are rare, recent reports have implicated Wnt signaling in the development and progression of human PDA. Here, we sought to address the role of β-catenin signaling in pancreas tumorigenesis. Methods: Using Cre/lox technology, we conditionally activated β-catenin in a subset of murine pancreatic cells in vivo. Results: Activation of β-catenin results in the formation of large pancreatic tumors at a high frequency in adult mice. These tumors resemble human SPN based on morphologic and immunohistochemical comparisons. Interestingly, stabilization of β-catenin blocks the formation of pancreatic intraepithelial neoplasia (PanIN) in the presence of an activating mutation in Kras that is known to predispose individuals to PDA. Instead, mice in which β-catenin and Kras are concurrently activated develop distinct ductal neoplasms that do not resemble PanIN lesions. Conclusions: These results demonstrate that activation of β-catenin is sufficient to induce pancreas tumorigenesis. Moreover, they indicate that the sequence in which oncogenic mutations are acquired has profound consequences on the phenotype of the resulting tumor.

Original languageEnglish
Pages (from-to)1288-1300
Number of pages13
Issue number4
StatePublished - Oct 2008
Externally publishedYes


FundersFunder number
National Institutes of HealthDK60533
American Diabetes Association
National Cancer InstituteR01CA112537
California Institute of Regenerative Medicine
Juvenile Diabetes Research Foundation Australia


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