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P120catenin facilitates pancreatic regeneration and monoallelic loss accelerates Kras-driven carcinogenesis and metastasis
Maximilian Reichert*1, 2, Basil Bakir1, 2, Christopher Hahn1, 2, Andrew D. Rhim3, Robert H. Vonderheide4, 7, Albert B. Reynolds5, Volkan Adsay6, Anil K. Rustgi1, 7
1Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania, United States, 2Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States, 3Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan, United States, 4Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, United States, 5Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States, 6Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, Georgia, United States, 7Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States and worldwide. It has been shown that p120catenin (p120ctn) loss or mislocalization correlates with poor patient survival. P120ctn is critical for epithelial integrity by regulating turnover of membrane-bound cadherins and downstream signaling via small RhoGTPases.
Method: In order to study p120catenin loss in the pancreas we crossed the Pdx1cre line with p120ctnfl/fl mice, challenged the pancreas with cerulein-induced pancreatitis and introduced a KrasG12D mutation in combination with a R26YFP reporter allele.
Results: p120ctnfl/fl mice display marked fatty degeneration but no cancer at 12 months of age. Interestingly, only the acinar compartment of the pancreas is affected although recombination was confirmed in all pancreatic lineages including islets of Langerhans. The relative amylase area in p120ctnfl/wt and p120ctnfl/fl mice is significantly decreased compared to wild-type controls. When challenging these mice with cerulein-induced acute pancreatitis, animals with monoallelic (p120ctnfl/wt) and biallelic (p120ctnfl/fl) loss of p120ctn show delayed regeneration and maintain an acinar-to-ductal phenotype. Remarkably, when introducing a mutant KrasG12D allele in combination with p120ctnfl/fl, mice are not viable. However, starting from 3 weeks of age Pdx1cre;p120ctnfl/wt;KrasG12D/+;R26YFP mice harbor the entire spectrum of PanIN (1-3) as well as cystic disease including mucinous cystic neoplasia and intraductal paplillary neoplasia. Within 20 weeks of age mice progress to PDAC with evident profound metastatic disease. These metastases (liver) are YFP positive (indicating recombination) but, surprisingly, retain p120ctn protein expression by immunofluorescence suggesting that no loss-of-heterozygosity (LOH) occurred. In addition, p120ctn co-localizes with E-cadherin at the plasma membrane. The absence of LOH suggests that one allele of p120ctn might be required to reestablish epithelial integrity at the metastatic site. When culturing wild-type, p120ctnfl/wt, and p120ctnfl/fl primary ductal epithelial cells in a three-dimensional system, only wild-type and p120ctnfl/wt are able to establish organized epithelial structures underscoring the in vivo results that one allele of p120ctn is sufficient to allow cells to revert back into an epithelial phenotype.
Conclusion: Taken together, p120ctn is required for proper pancreatic regeneration and monoallelic loss of p120ctn in combination with KrasG12D accelerates metastatic PDAC progression. The data indicate that monoallelic loss of p120ctn facilitates cellular plasticity. Our mouse model represents a novel, innovative and physiologically relevant tool to study pancreatic carcinogenesis and metastasis as well as EMT-MET plasticity.
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