title: p53 status determines the role of autophagy in pancreatic tumour development.
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.
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Mathias T
authors.initials: MT
authors.lastname: Rosenfeldt
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Jim
authors.initials: J
authors.lastname: O'Prey
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Morton
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Nixon
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Gillian
authors.initials: G
authors.lastname: MacKay
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Agata
authors.initials: A
authors.lastname: Mrowinska
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Amy
authors.initials: A
authors.lastname: Au
authors.affiliation: Institute of Cancer Studies, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G611BD, UK.
authors.forename: Taranjit Singh
authors.initials: TS
authors.lastname: Rai
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Liang
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Ridgway
authors.affiliation: Institute of Cancer Studies, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G611BD, UK.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Adams
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Kurt I
authors.initials: KI
authors.lastname: Anderson
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Eyal
authors.initials: E
authors.lastname: Gottlieb
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Ryan
mesh_terms: D000483:Alleles; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D016158:Genes, p53 / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology; D055432:Metabolomics; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics; D015689:Oncogene Protein p21(ras) / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010427:Pentose Phosphate Pathway / Q000235:genetics; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: C495773:Atg5 protein, mouse; C502661:Atg7 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D016159:Tumor Suppressor Protein p53; D006886:Hydroxychloroquine; D015689:Oncogene Protein p21(ras); D000071193:Autophagy-Related Protein 7; D005947:Glucose