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

作者：Jennifer P. Morton, Paul Timpson, Saadia A. Karim, Rachel A. Ridgway, Dimitris Athineos, Brendan J. Doyle, Nigel Balfour Jamieson, Karin A. Oien, Andrew M. Lowy, Valerie G. Brunton, Margaret C. Frame, Thomas R. Jeffry Evans, Owen James Sansom · 发表于：Proceedings of the National Academy of Sciences · 年份：2009 · DOI：10.1073/pnas.0908428107 · 被引用次数：691 · 研究领域：Pancreatic and Hepatic Oncology Research、Cancer-related Molecular Pathways、Epigenetics and DNA Methylation

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, 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 find 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 progression 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 find that despite similar kinetics of primary tumor formation, mutant p53(R172H), as compared with genetic loss of p53, specifically promotes metastasis. Moreover, only mutant p53(R172H)-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 ...