As malignant tumours develop, they interact intimately with their microenvironment and can activate autophagy1, a catabolic process which provides nutrients during starvation. How tumours regulate autophagy in vivo and whether autophagy affects tumour growth is controversial2. Here we demonstrate, using a well characterized Drosophila melanogaster malignant tumour model3,4, that non-cell-autonomous autophagy is induced both in the tumour microenvironment and systemically in distant tissues. Tumour growth can be pharmacologically restrained using autophagy inhibitors, and early-stage tumour growth and invasion are genetically dependent on autophagy within the local tumour microenvironment. Induction of autophagy is mediated by Drosophila tumour necrosis factor and interleukin-6-like signalling from metabolically stressed tumour cells, whereas tumour growth depends on active amino acid transport. We show that dormant growth-impaired tumours from autophagy-deficient animals reactivate tumorous growth when transplanted into autophagy-proficient hosts. We conclude that transformed cells engage surrounding normal cells as active and essential microenvironmental contributors to early tumour growth through nutrient-generating autophagy.

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We thank M. Smestad, E. Rønning, I. D. Rein, M. Bostad and T. Stokke at the flow cytometry core facility at the Radium Hospital for technical support; K. Liestøl for advice on statistics; T. Vaccari, H. Jasper, C. Gonzales, S. B. Thoresen, and the H. Stenmark laboratory for discussions; E. Baehrecke, T. Xu, T. Igaki, K. Basler, G. Halder, D. Bohmann, M. Vidal, M. Zeidler, T. P. Neufeld, I. Salecker, M. Uhlirova and T. Vaccari, Bloomington Stock Centre, the TRiP at Harvard Medical School (NIH/NIGMS R01-GM084947), VDRC, Pacman library project, and the Developmental Studies Hybridoma Bank for fly stocks and reagents; and H. Richardson and J. Manent for communication before publication. This work was supported in part by the Research Council of Norway through its Centres of Excellence funding scheme (179571) to H.S., by grants from the Norwegian Cancer Society (PK01-2009-0386) to T.E.R., (145517) to F.O.F., (71043-PR-2006-0320) and to T.J. A career stipend from The Southern and Eastern Regional Health Authority (2015016) is held by T.E.R., FRIBIO and FRIBIOMED programs of the Norwegian Research Council (196898, 214448) are held by T.J. and A.J. NIH RO1 GM090150 is held by D.B. EU FP7-People-2013-COFUND (no. 609020—Scientia Fellows) is held by M.M.R. Momentum (LP2014-2) is held by G.J. A grant from the Simon Fougner Hartmanns Foundation (for Seahorse instrument acquisition) is held by T.A.T.

Author information

Author notes

    • Rojyar Khezri
    •  & Fergal O’Farrell

    These authors contributed equally to this work.


  1. Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway

    • Nadja S. Katheder
    • , Rojyar Khezri
    • , Fergal O’Farrell
    • , Sebastian W. Schultz
    • , Ashish Jain
    • , Mohammed M. Rahman
    • , Kay O. Schink
    • , Andreas Brech
    • , Harald Stenmark
    •  & Tor Erik Rusten
  2. Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway

    • Nadja S. Katheder
    • , Rojyar Khezri
    • , Fergal O’Farrell
    • , Sebastian W. Schultz
    • , Ashish Jain
    • , Mohammed M. Rahman
    • , Kay O. Schink
    • , Andreas Brech
    • , Harald Stenmark
    •  & Tor Erik Rusten
  3. Molecular Cancer Research Group, Institute of Medical Biology, UiT - The Arctic University of Norway, 9037 Tromsø, Norway

    • Ashish Jain
    •  & Terje Johansen
  4. Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway

    • Theodossis A. Theodossiou
  5. Institute of Genetics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, H-6726 Hungary

    • Gábor Juhász
  6. Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Budapest H-1117, Hungary

    • Gábor Juhász
  7. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720-3200, USA

    • David Bilder


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N.S.K., H.S., D.B., T.J. and T.E.R. designed the research; N.S.K., R.K., F.O.F, A.J., S.W.S., M.M.R., K.O.S., T.A.T., A.B. and T.E.R., performed experiments and analysed the data; G.J. developed transgenic autophagy reporter animals; and N.S.K., H.S., D.B., and T.E.R. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Tor Erik Rusten.

Reviewer Information

Nature thanks T. Igaki, H. Zhang and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    Supplementary Information

    This file contains the uncropped western blots and Supplementary Methods (a list of detailed genotypes for each figure).

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