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 MaHeng Yang, Helmuth Popper, Lukas Kenner, Guido Kroemer, Josef M. Penninger

    Research output: Contribution to journalArticlepeer-review

    366 Citations (Scopus)

    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 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.

    Original languageEnglish
    Article number3056
    JournalNature Communications
    Volume5
    DOIs
    Publication statusPublished - 20 Jan 2014

    Cite this