P53 status determines the role of autophagy in pancreatic tumour development

Mathias T. Rosenfeldt, Jim O'Prey, Jennifer P. Morton, Colin Nixon, Gillian Mackay, Agata Mrowinska, Amy Au, Taranjit Singh Rai, Liang Zheng, Rachel Ridgway, Peter D. Adams, Kurt I. Anderson, Eyal Gottlieb, Owen J. Sansom, Kevin M. Ryan

Research output: Contribution to journalArticle

320 Citations (Scopus)

Abstract

Macroautophagy (hereafter referred to as autophagy) is a process in which organelles termed autophagosomes deliver cytoplasmic constituents to lysosomes for degradation. Autophagy has a major role in cellular homeostasis and has been implicated in various forms of human disease. The role of autophagy in cancer seems to be complex, with reports indicating both pro-tumorigenic and tumour-suppressive roles. Here we show, in a humanized genetically-modified mouse model of pancreatic ductal adenocarcinoma (PDAC), that autophagy's role in tumour development is intrinsically connected to the status of the tumour suppressor p53. Mice with pancreases containing an activated oncogenic allele of Kras (also called Ki-Ras) - the most common mutational event in PDAC - develop a small number of pre-cancerous lesions that stochastically develop into PDAC over time. However, mice also lacking the essential autophagy genes Atg5 or Atg7 accumulate low-grade, pre-malignant pancreatic intraepithelial neoplasia lesions, but progression to high-grade pancreatic intraepithelial neoplasias and PDAC is blocked. In marked contrast, in mice containing oncogenic Kras and lacking p53, loss of autophagy no longer blocks tumour progression, but actually accelerates tumour onset, with metabolic analysis revealing enhanced glucose uptake and enrichment of anabolic pathways, which can fuel tumour growth. These findings provide considerable insight into the role of autophagy in cancer and have important implications for autophagy inhibition in cancer therapy. In this regard, we also show that treatment of mice with the autophagy inhibitor hydroxychloroquine, which is currently being used in several clinical trials, significantly accelerates tumour formation in mice containing oncogenic Kras but lacking p53.

LanguageEnglish
Pages296-300
Number of pages5
JournalNature
Volume504
Issue number7479
DOIs
Publication statusPublished - 6 Dec 2013

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Autophagy
Neoplasms
Adenocarcinoma
Hydroxychloroquine
Essential Genes
Lysosomes
Organelles
Pancreas
Homeostasis
Alleles
Clinical Trials

Cite this

Rosenfeldt, M. T., O'Prey, J., Morton, J. P., Nixon, C., Mackay, G., Mrowinska, A., ... Ryan, K. M. (2013). P53 status determines the role of autophagy in pancreatic tumour development. Nature, 504(7479), 296-300. https://doi.org/10.1038/nature12865
Rosenfeldt, Mathias T. ; O'Prey, Jim ; Morton, Jennifer P. ; Nixon, Colin ; Mackay, Gillian ; Mrowinska, Agata ; Au, Amy ; Rai, Taranjit Singh ; Zheng, Liang ; Ridgway, Rachel ; Adams, Peter D. ; Anderson, Kurt I. ; Gottlieb, Eyal ; Sansom, Owen J. ; Ryan, Kevin M. / P53 status determines the role of autophagy in pancreatic tumour development. In: Nature. 2013 ; Vol. 504, No. 7479. pp. 296-300.
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abstract = "Macroautophagy (hereafter referred to as autophagy) is a process in which organelles termed autophagosomes deliver cytoplasmic constituents to lysosomes for degradation. Autophagy has a major role in cellular homeostasis and has been implicated in various forms of human disease. The role of autophagy in cancer seems to be complex, with reports indicating both pro-tumorigenic and tumour-suppressive roles. Here we show, in a humanized genetically-modified mouse model of pancreatic ductal adenocarcinoma (PDAC), that autophagy's role in tumour development is intrinsically connected to the status of the tumour suppressor p53. Mice with pancreases containing an activated oncogenic allele of Kras (also called Ki-Ras) - the most common mutational event in PDAC - develop a small number of pre-cancerous lesions that stochastically develop into PDAC over time. However, mice also lacking the essential autophagy genes Atg5 or Atg7 accumulate low-grade, pre-malignant pancreatic intraepithelial neoplasia lesions, but progression to high-grade pancreatic intraepithelial neoplasias and PDAC is blocked. In marked contrast, in mice containing oncogenic Kras and lacking p53, loss of autophagy no longer blocks tumour progression, but actually accelerates tumour onset, with metabolic analysis revealing enhanced glucose uptake and enrichment of anabolic pathways, which can fuel tumour growth. These findings provide considerable insight into the role of autophagy in cancer and have important implications for autophagy inhibition in cancer therapy. In this regard, we also show that treatment of mice with the autophagy inhibitor hydroxychloroquine, which is currently being used in several clinical trials, significantly accelerates tumour formation in mice containing oncogenic Kras but lacking p53.",
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Rosenfeldt, MT, O'Prey, J, Morton, JP, Nixon, C, Mackay, G, Mrowinska, A, Au, A, Rai, TS, Zheng, L, Ridgway, R, Adams, PD, Anderson, KI, Gottlieb, E, Sansom, OJ & Ryan, KM 2013, 'P53 status determines the role of autophagy in pancreatic tumour development', Nature, vol. 504, no. 7479, pp. 296-300. https://doi.org/10.1038/nature12865

P53 status determines the role of autophagy in pancreatic tumour development. / Rosenfeldt, Mathias T.; O'Prey, Jim; Morton, Jennifer P.; Nixon, Colin; Mackay, Gillian; Mrowinska, Agata; Au, Amy; Rai, Taranjit Singh; Zheng, Liang; Ridgway, Rachel; Adams, Peter D.; Anderson, Kurt I.; Gottlieb, Eyal; Sansom, Owen J.; Ryan, Kevin M.

In: Nature, Vol. 504, No. 7479, 06.12.2013, p. 296-300.

Research output: Contribution to journalArticle

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AU - Rosenfeldt, Mathias T.

AU - O'Prey, Jim

AU - Morton, Jennifer P.

AU - Nixon, Colin

AU - Mackay, Gillian

AU - Mrowinska, Agata

AU - Au, Amy

AU - Rai, Taranjit Singh

AU - Zheng, Liang

AU - Ridgway, Rachel

AU - Adams, Peter D.

AU - Anderson, Kurt I.

AU - Gottlieb, Eyal

AU - Sansom, Owen J.

AU - Ryan, Kevin M.

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Rosenfeldt MT, O'Prey J, Morton JP, Nixon C, Mackay G, Mrowinska A et al. P53 status determines the role of autophagy in pancreatic tumour development. Nature. 2013 Dec 6;504(7479):296-300. https://doi.org/10.1038/nature12865