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Mutant  p53  drives metastasis and overcomes growth arrest/senescence in pancreatic cancer
 

1.   Jennifer P. Mortona,b, Paul Timpsona, Saadia A. Karima, Rachel A. Ridgwaya, Dimitris Athineosa,b, Brendan Doylea, Nigel B. Jamiesonb, Karin A. Oienb, Andrew M. Lowyc, Valerie G. Bruntond, Margaret C. Framed, T. R. Jeffry Evansa,b and Owen J. Sansoma,1

1.   aBeatson Institute for Cancer Research, Glasgow G61 1BD, United Kingdom;

2.   bCentre for Oncology and Applied Pharmacology, Division of Cancer Sciences and Molecular Pathology, University of Glasgow, Glasgow G61 1BD, United Kingdom;

3.   cDivision of Surgical Oncology, Moores UCSD Cancer Center, La Jolla, CA 92093;

4.   dEdinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, United Kingdom

1.   Edited by Laura Attardi, Stanford University, Stanford, CA, and accepted by the Editorial Board November 12, 2009 (received for review July 28, 2009)

Abstract

TP53 mutation occurs in 50–75% of human pancreatic ductal adenocarcinomas (PDAC) following an initiating activating mutation in the KRAS gene. These p53 mutations frequently result in expression of a stable protein, p53R175H, rather than complete loss of protein expression. In this study we elucidate the functions of mutant p53 (Trp53R172H), compared to knockout p53 (Trp53fl), in a mouse model of PDAC. First we find that although KrasG12D is one of the major oncogenic drivers of PDAC, most KrasG12D-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 KrasG12D-expressing cells and drives rapid progression of these premalignant lesions to PDAC. This progression is consistent with failed growth arrest and/or senescence of premalignant lesions, since a mutant of p53, p53R172P, which can still induce p21 and cell cycle arrest, is resistant to PDAC formation. Second, we find that despite similar kinetics of primary tumor formation, mutant p53R172H, as compared with genetic loss of p53, specifically promotes metastasis. Moreover, only mutant p53R172H-expressing tumor cells exhibit invasive activity in an in vitro assay. Importantly, in human PDAC, p53 accumulation significantly correlates with lymph node metastasis. In summary, by using ‘knock-in’ mutations of Trp53 we have identified two critical acquired functions of a stably expressed mutant form of p53 that drive PDAC; first, an escape from KrasG12D-induced senescence/growth arrest and second, the promotion of metastasis                

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