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Both$p16^{Ink4a}$and the$p19^{Arf}-p53$Pathway Constrain Progression of Pancreatic Adenocarcinoma in the Mouse

Activating KRAS mutations and$p16^{Ink4a}$inactivation are near universal events in human pancreatic ductal adenocarcinoma (PDAC). In mouse models,$Kras^{G12D}$initiates formation of premalignant pancreatic ductal lesions, and loss of either$Ink4a/Arf$($p16^{Ink4a}/p19^{Arf}$) or p53 enables their m...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2006-04, Vol.103 (15), p.5947-5952
Main Authors: Bardeesy, Nabeel, Aguirre, Andrew J., Chu, Gerald C., Cheng, Kuang-hung, Lopez, Lyle V., Hezel, Aram F., Feng, Bin, Brennan, Cameron, Weissleder, Ralph, Mahmood, Umar, Hanahan, Douglas, Redston, Mark S., Chin, Lynda, DePinho, Ronald A.
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Language:English
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Summary:Activating KRAS mutations and$p16^{Ink4a}$inactivation are near universal events in human pancreatic ductal adenocarcinoma (PDAC). In mouse models,$Kras^{G12D}$initiates formation of premalignant pancreatic ductal lesions, and loss of either$Ink4a/Arf$($p16^{Ink4a}/p19^{Arf}$) or p53 enables their malignant progression. As recent mouse modeling studies have suggested a less prominent role for$p16^{Ink4a}$in constraining malignant progression, we sought to assess the pathological and genomic impact of inactivation of$p16^{Ink4a}$,$p19^{Arf}$, and/or p53 in the$Kras^{G12D}$model. Rapidly progressive PDAC was observed in the setting of homozygous deletion of either p53 or$p16^{Ink4a}$, the latter with intact germ-line p53 and$p19^{Arf}$sequences. Additionally,$Kras^{G12D}$in the context of heterozygosity either for p53 plus$p16^{Ink4a}$or for$p16^{Ink4a}/p19^{Arf}$produced PDAC with longer latency and greater propensity for distant metastases relative to mice with homozygous deletion of p53 or$p16^{Ink4a}/p19^{Arf}$. Tumors from the double-heterozygous cohorts showed frequent$p16^{Ink4a}$inactivation and loss of either p53 or$p19^{Arf}$. Different genotypes were associated with specific histopathologic characteristics, most notably a trend toward less differentiated features in the homozygous$p16^{Ink4a}$/p19^{Arf}$mutant model. High-resolution genomic analysis revealed that the tumor suppressor genotype influenced the specific genomic patterns of these tumors and showed overlap in regional chromosomal alterations between murine and human PDAC. Collectively, our results establish that disruptions of$p16^{Ink4a}$and the$p19^{ARF}-p53$circuit play critical and cooperative roles in PDAC progression, with specific tumor suppressor genotypes provocatively influencing the tumor biological phenotypes and genomic profiles of the resultant tumors.
ISSN:0027-8424
DOI:10.1073/pnas.0601273103