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Unformatted text preview: Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer Jennifer P. Morton a,b , Paul Timpson a , Saadia A. Karim a , Rachel A. Ridgway a , Dimitris Athineos a,b , Brendan Doyle a , Nigel B. Jamieson b , Karin A. Oien b , Andrew M. Lowy c , Valerie G. Brunton d , Margaret C. Frame d , T. R. Jeffry Evans a,b , and Owen J. Sansom a,1 a Beatson Institute for Cancer Research, Glasgow G61 1BD, United Kingdom; b Centre for Oncology and Applied Pharmacology, Division of Cancer Sciences and Molecular Pathology, University of Glasgow, Glasgow G61 1BD, United Kingdom; c Division of Surgical Oncology, Moores UCSD Cancer Center, La Jolla, CA 92093; and d Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, United Kingdom Edited by Laura Attardi, Stanford University, Stanford, CA, and accepted by the Editorial Board November 12, 2009 (received for review July 28, 2009) TP53 mutation occurs in 50 – 75% of human pancreatic ductal ad- enocarcinomas (PDAC) following an initiating activating mutation in the KRAS gene. These p53 mutations frequently result in ex- pression of a stable protein, p53 R175H , rather than complete loss of protein expression. In this study we elucidate the functions of mutant p53 ( Trp53 R172H ), compared to knockout p53 ( Trp53 ﬂ ), in a mouse model of PDAC. First we fi nd that although Kras G12D is one of the major oncogenic drivers of PDAC, most Kras G12D-expressing pancreatic cells are selectively lost from the tissue, and those that remain form premalignant lesions. Loss, or mutation, of Trp53 allows retention of the Kras G12D-expressing cells and drives rapid progression of these premalignant lesions to PDAC. This progres- sion is consistent with failed growth arrest and/or senescence of premalignant lesions, since a mutant of p53, p53 R172P , which can still induce p21 and cell cycle arrest, is resistant to PDAC formation. Second, we fi nd that despite similar kinetics of primary tumor formation, mutant p53 R172H , as compared with genetic loss of p53, speci fi cally promotes metastasis. Moreover, only mutant p53 R172H-expressing tumor cells exhibit invasive activity in an in vitro assay. Importantly, in human PDAC, p53 accumulation signif- icantly correlates with lymph node metastasis. In summary, by using ‘ knock-in ’ mutations of Trp53 we have identi fi ed two critical acquired functions of a stably expressed mutant form of p53 that drive PDAC; fi rst, an escape from Kras G12D-induced senescence/ growth arrest and second, the promotion of metastasis. Kras | metastasis | p53 | pancreatic cancer | senescence P ancreatic ductal adenocarcinoma (PDAC) is the fi fth leading cause of cancer deaths in Europe and the United States, with an estimated 5-year overall survival of less than 5% (1, 2). Poor prog- nosis results from the aggressive nature of the disease, with as many as 90% of patients at the time of diagnosis harboring unresectable...
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- Winter '08
- Biology, mutant p53, Pdx1-Cre-GFP