RRC ID 28431
Author 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.
Title p53 status determines the role of autophagy in pancreatic tumour development.
Journal Nature
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.
Volume 504(7479)
Pages 296-300
Published 2013-12-12
DOI 10.1038/nature12865
PII nature12865
PMID 24305049
MeSH Alleles Animals Autophagy* / drug effects Autophagy* / genetics Autophagy-Related Protein 5 Autophagy-Related Protein 7 Carcinoma, Pancreatic Ductal / genetics* Carcinoma, Pancreatic Ductal / metabolism Carcinoma, Pancreatic Ductal / pathology* Cell Line, Tumor Disease Models, Animal Genes, p53 / genetics* Glucose / metabolism Glycolysis / genetics Humans Hydroxychloroquine / pharmacology Metabolomics Mice Mice, 129 Strain Mice, Inbred C57BL Microtubule-Associated Proteins / genetics Oncogene Protein p21(ras) / genetics Pancreatic Neoplasms / genetics* Pancreatic Neoplasms / metabolism Pancreatic Neoplasms / pathology* Pentose Phosphate Pathway / genetics Precancerous Conditions / genetics Precancerous Conditions / metabolism Precancerous Conditions / pathology Survival Analysis Tumor Suppressor Protein p53 / deficiency Tumor Suppressor Protein p53 / genetics* Tumor Suppressor Protein p53 / metabolism
IF 42.779
Times Cited 372
Mice RBRC02975