p53 status determines the role of autophagy in pancreatic tumour development

Rosenfeldt, M.T. et al. (2013) p53 status determines the role of autophagy in pancreatic tumour development. Nature, 504(7479), pp. 296-300. (doi: 10.1038/nature12865)

Abstract

Macroautophagy (hereafter referred to as autophagy) is a process in which organelles termed autophagosomes deliver cytoplasmic constituents to lysosomes for degradation1. Autophagy has a major role in cellular homeostasis and has been implicated in various forms of human disease2, 3, 4. The role of autophagy in cancer seems to be complex, with reports indicating both pro-tumorigenic and tumour-suppressive roles3, 5, 6, 7, 8, 9, 10, 11, 12. 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 PDAC13—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 trials14, significantly accelerates tumour formation in mice containing oncogenic Kras but lacking p53.

• Item Type: Articles (Letter)
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Rai, Dr Taranjit and Anderson, Professor Kurt and Ryan, Professor Kevin and Nixon, Mr Colin and Zheng, Mr Liang and Rosenfeldt, Dr Mathias and Ridgway, Dr Rachel and Gottlieb, Professor Eyal and Adams, Professor Peter and Mackay, Dr Gillian and Mrowinska, Ms Agata and O'Prey, Mr James and Morton, Professor Jen and Sansom, Professor Owen
• Authors: Rosenfeldt, M.T., O'Prey, J., Morton, J.P., Nixon, C., MacKay, G., Mrowinska, A., Au, A., Rai, T.S., Zheng, L., Ridgway, R., Adams, P.D., Anderson, K.I., Gottlieb, E., Sansom, O.J., and Ryan, K.M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature
• Publisher: Nature Publishing Group
• ISSN: 0028-0836
• ISSN (Online): 1476-4687