A dual role for autophagy in a murine model of lung cancer

Shuan Rao, Luigi Tortola, Thomas Perlot, Gerald Wirnsberger, Maria Novatchkova, Roberto Nitsch, Peter Sykacek, Lukas Frank, Daniel Schramek, Vukoslav Komnenovic, Verena Sigl, Karin Aumayr, Gerald Schmauss, Nicole Fellner, Stephan Handschuh, Martin Glösmann, Pawel Pasierbek, Michaela Schlederer, Guenter P. Resch, Yuting Ma, Heng Yang, Helmuth Popper, Lukas Kenner, Guido Kroemer () and Josef M. Penninger ()
Additional contact information
Shuan Rao: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Luigi Tortola: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Thomas Perlot: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Gerald Wirnsberger: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Maria Novatchkova: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Roberto Nitsch: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Peter Sykacek: University of Natural Resources and Life Sciences
Lukas Frank: Medical University Vienna
Daniel Schramek: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Vukoslav Komnenovic: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Verena Sigl: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Karin Aumayr: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Gerald Schmauss: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Nicole Fellner: Campus Science Support Facilities
Stephan Handschuh: VetCore Facility for Research, University of Veterinary Medicine
Martin Glösmann: VetCore Facility for Research, University of Veterinary Medicine
Pawel Pasierbek: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Michaela Schlederer: Ludwig Boltzman Institute for Cancer Research (LBI-CR)
Guenter P. Resch: Campus Science Support Facilities
Yuting Ma: INSERM U848, 39 rue Camille Desmoulins
Heng Yang: INSERM U848, 39 rue Camille Desmoulins
Helmuth Popper: Institute of Pathology, Research Unit Molecular Lung and Pleura Pathology, Medical University Graz
Lukas Kenner: Ludwig Boltzman Institute for Cancer Research (LBI-CR)
Guido Kroemer: INSERM U848, 39 rue Camille Desmoulins
Josef M. Penninger: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: Abstract 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 KRasG12D-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 KRasG12D-driven lung tumours is markedly accelerated. Mechanistically, increased oncogenesis maps to regulatory T cells. These results demonstrate that, in KRasG12D-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.

Date: 2014
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DOI: 10.1038/ncomms4056

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