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

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

doi:10.1073/pnas.0908428107

Cited by 657Cancer-related Molecular PathwaysPancreatic and Hepatic Oncology ResearchTelomeres, Telomerase, and Senescence

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

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Morton, Jennifer P., Timpson, Paul, Karim, Saadia A., Ridgway, Rachel A., Athineos, Dimitris, Doyle, Brendan, Jamieson, Nigel B., Oien, Karin A. +5 more·2010·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0908428107PMC PMC2806749

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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, 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 p53 that drive PDAC; first, an escape from Kras G12D -induced senescence/growth arrest and second, the promotion of metastasis.

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Mutant p53 accumulation promoted metastasis and correlated with lymph node metastasis in human PDAC samples.
“Mutant p53 accumulation promoted metastasis and was validated in human PDAC samples, where p53 accumulation correlated with lymph node metastasis.”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [19]
Loss of p53 allowed retention of KrasG12D-expressing cells, facilitating tumor formation and escape from KRAS-induced growth arrest.
“Loss of p53 allowed the retention of KrasG12D-expressing cells, facilitating tumor formation and escape from KRAS-induced growth arrest.”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [19]
In vitro invasion assays confirmed the intrinsic role of mutant p53 in driving metastasis.
“In vitro invasion assays confirmed the intrinsic role of mutant p53 in driving metastasis [19].”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [19]
In genetically modified mice, coexisting KRAS mutation and mutant p53 (Trp53R172H) led to rapid PDAC onset with liver metastasis.
“Genetically modified mice revealed distinct roles of mutant p53 in PDAC progression, demonstrating that coexisting KRAS mutation and mutant p53 (Trp53R172H) led to rapid PDAC onset with liver metastasis.”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [19]
KRasG12D is a potent oncogene in pancreas, but its tumourigenic properties are restrained by its ability to cause OIS, observed in premalignant PanIN lesions.
“KRas G12D is a potent oncogene in pancreas, but its tumourigenic properties are restrained by its ability to cause OIS, observed in premalignant PanIN lesions 24 .”
From A complex secretory program orchestrated by the inflammasome controls paracrine senescence (2013) · cites this paper as [24]

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Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,178 · cited 1× · see citing works
“Despite its role as an oncoprotein,Kras induces a senescence program innormalhumanandmousecells in culture, and this canbe prevented by inactivation of either p53 or p16 (13).”
Background
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Kuilman, T., Michaloglou, C., Vredeveld, L. C. W., Douma, S., van Doorn, R., Desmet, C. J., Aarden, L. A., Mooi, W. J., & Peeper, D. S. (2008) · Cell · doi:10.1016/j.cell.2008.03.039 · Cited by 2,086 · see citing works
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Authors: Morton, J. P., Timpson, P., Karim, S. A., Ridgway, R. A., Athineos, D., Doyle, B., Jamieson, N. B., Oien, K. A., Lowy, A. M., Brunton, V. G., Frame, M. C., Evans, T. R. J., & Sansom, O. J.
Affiliations: Cancer Research UK Scotland Institute (GB)
University of Glasgow (GB)
University of California San Diego (US)
Edinburgh Cancer Research (GB)
Corresponding author: Sansom, Owen J.
ORCID: Morton, Jennifer P.
Timpson, Paul
Karim, Saadia A.
Ridgway, Rachel A.
Athineos, Dimitris
Jamieson, Nigel B.
Oien, Karin A.
Lowy, Andrew M.
Brunton, Valerie G.
Frame, Margaret C.
Evans, T. R. Jeffry
Sansom, Owen J.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2010-01-05
Volume: 107
Issue: 1
Pages: 246-251
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0908428107
PMC: PMC2806749
OpenAlex: W2039210293
Cited by: 657
References: 9
Citations by year: 2026: 18 · 2025: 37 · 2024: 40 · 2023: 49 · 2022: 51 · 2021: 54 · 2020: 46 · 2019: 43 · 2018: 37 · 2017: 48 · 2016: 38 · 2015: 44 · 2014: 48 · 2013: 28 · 2012: 31
FWCI: 12.50
Type: journal article
Language: en
Update notices: correction (2022-04-26)
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Cancer Research UK (C157/A11473)
University of Texas MD Anderson Cancer Center
Topics: Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Keywords: mutant p53, pancreatic ductal adenocarcinoma, KRAS G12D, senescence escape, growth arrest, metastasis, lymph node metastasis, tumor invasion, p21, precancerous lesions, knock-in mice, p53 R172H
MeSH terms: Animals, Cell Cycle, Humans, Mutation, Neoplasm Metastasis, Recombinant Fusion Proteins, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Cellular Senescence, Genes, Reporter, Carcinoma, Pancreatic Ductal, Microarray Analysis, Mice

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

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