A dual role for autophagy in a murine model of lung cancer.
Autophagy is a mechanism by which starving cells can control their energy requirements and metabolic states, thus facilitating the survival of cells in stressful environments, in particular in the pathogenesis of cancer. Here we report that tissue-specific inactivation of Atg5, essential for the formation of autophagosomes, markedly impairs the progression of KRas(G12D)-driven lung cancer, resulting in a significant survival advantage of tumour-bearing mice. Autophagy-defective lung cancers exhibit impaired mitochondrial energy homoeostasis, oxidative stress and a constitutively active DNA damage response. Genetic deletion of the tumour suppressor p53 reinstates cancer progression of autophagy-deficient tumours. Although there is improved survival, the onset of Atg5-mutant KRas(G12D)-driven lung tumours is markedly accelerated. Mechanistically, increased oncogenesis maps to regulatory T cells. These results demonstrate that, in KRas(G12D)-driven lung cancer, Atg5-regulated autophagy accelerates tumour progression; however, autophagy also represses early oncogenesis, suggesting a link between deregulated autophagy and regulatory T cell controlled anticancer immunity.
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
Shuan
S
Rao
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
Luigi
L
Tortola
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
Thomas
T
Perlot
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
Gerald
G
Wirnsberger
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
Maria
M
Novatchkova
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
Roberto
R
Nitsch
Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna 1180, Austria.
Peter
P
Sykacek
Department of Medical and Chemical Laboratory Diagnostics, Medical University Vienna, Vienna 1090, Austria.
Lukas
L
Frank
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
Daniel
D
Schramek
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
Vukoslav
V
Komnenovic
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
Verena
V
Sigl
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
Karin
K
Aumayr
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
Gerald
G
Schmauss
Campus Science Support Facilities, Vienna 1030, Austria.
Nicole
N
Fellner
VetCore Facility for Research, University of Veterinary Medicine, Vienna 1210, Austria.
Stephan
S
Handschuh
VetCore Facility for Research, University of Veterinary Medicine, Vienna 1210, Austria.
Martin
M
Glösmann
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
Pawel
P
Pasierbek
1] Ludwig Boltzman Institute for Cancer Research (LBI-CR), Vienna 1090, Austria [2] Clinical Institute of Pathology, Medical University Vienna, Vienna 1090, Austria.
Michaela
M
Schlederer
Campus Science Support Facilities, Vienna 1030, Austria.
Guenter P
GP
Resch
1] INSERM U848, 39 rue Camille Desmoulins, Villejuif F-94805, France [2] Gustave Roussy Cancer Campus, Villejuif F-94805, France [3] Faculté de Médecine, Université Paris Sud/Paris 11, Le Kremlin Bicêtre F-94270, France.
Yuting
Y
Ma
1] INSERM U848, 39 rue Camille Desmoulins, Villejuif F-94805, France [2] Gustave Roussy Cancer Campus, Villejuif F-94805, France [3] Faculté de Médecine, Université Paris Sud/Paris 11, Le Kremlin Bicêtre F-94270, France.
Heng
H
Yang
Institute of Pathology, Research Unit Molecular Lung and Pleura Pathology, Medical University Graz, Graz 8036, Austria.
Helmuth
H
Popper
1] Ludwig Boltzman Institute for Cancer Research (LBI-CR), Vienna 1090, Austria [2] Clinical Institute of Pathology, Medical University Vienna, Vienna 1090, Austria.
Lukas
L
Kenner
1] INSERM U848, 39 rue Camille Desmoulins, Villejuif F-94805, France [2] Gustave Roussy Cancer Campus, Villejuif F-94805, France [3] Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif F-94805, France [4] Equipe 11 labellisée par la Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris F-75006, France [5] Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris F-75015, France [6] Université Paris Descartes, Sorbonne Paris Cité, Paris F-75006, France.
Guido
G
Kroemer
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
Josef M
JM
Penninger
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D008175:Lung Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000473:pathology / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology
C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D016159:Tumor Suppressor Protein p53