Journal Article

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

Sansom, Owen J, Athineos, Dimitris, Ridgway, Rachel A, Oien, Karin A, Lowy, Andrew M, Brunton, Valerie G, Doyle, Brendan, Morton, Jennifer P, Jamieson, Nigel B, Evans, T.R. Jeffry, Karim, Saadia A, Timpson, Paul, Frame, Margaret C

2010

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: adenocarcinoma / animal models / Animals / Biological Sciences / Carcinoma, Pancreatic Ductal - genetics / Carcinoma, Pancreatic Ductal - pathology / Cell cycle / Cell Cycle - physiology / cell cycle checkpoints / Cellular senescence / Cellular Senescence - genetics / Gene expression / genes / Genes, Reporter / Genetic mutation / Humans / Imaging / in vitro studies / Lesions / lymph nodes / Metastasis / Mice / Microarray Analysis / Mutants / Mutation / neoplasm cells / Neoplasm Metastasis - genetics / Neoplasm Metastasis - pathology / Pancreas / Pancreatic cancer / Pancreatic cells / Pancreatic neoplasms / protein depletion / protein synthesis / Proteins / Proto-Oncogene Proteins p21(ras) - genetics / Proto-Oncogene Proteins p21(ras) - metabolism / Recombinant Fusion Proteins - genetics / Recombinant Fusion Proteins - metabolism / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism / Tumors