Abstract

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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References

  1. 1.

    & Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012)

  2. 2.

    et al. Autophagy in malignant transformation and cancer progression. EMBO J. 34, 856–880 (2015)

  3. 3.

    & A genetic screen in Drosophila for metastatic behavior. Science 302, 1227–1231 (2003)

  4. 4.

    & scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J. 22, 5769–5779 (2003)

  5. 5.

    & Mosaic analysis with a repressible cell marker (MARCM) for Drosophila neural development. Trends Neurosci. 24, 251–254 (2001)

  6. 6.

    et al. Relationship between growth arrest and autophagy in midgut programmed cell death in Drosophila. Cell Death Differ. 19, 1299–1307 (2012)

  7. 7.

    & JNK- and Fos-regulated Mmp1 expression cooperates with Ras to induce invasive tumors in Drosophila. EMBO J. 25, 5294–5304 (2006)

  8. 8.

    et al. Systemic organ wasting induced by localized expression of the secreted insulin/IGF antagonist ImpL2. Dev. Cell 33, 36–46 (2015)

  9. 9.

    & Malignant Drosophila tumors interrupt insulin signaling to induce cachexia-like wasting. Dev. Cell 33, 47–55 (2015)

  10. 10.

    , & Role of autophagy in glycogen breakdown and its relevance to chloroquine myopathy. PLoS Biol. 11, e1001708 (2013)

  11. 11.

    , , & Autophagy regulates tissue overgrowth in a context-dependent manner. Oncogene 34, 3369–3376 (2015)

  12. 12.

    et al. Autophagy is required for glucose homeostasis and lung tumor maintenance. Cancer Discov. 4, 914–927 (2014)

  13. 13.

    et al. Anterograde Jelly belly and Alk receptor tyrosine kinase signaling mediates retinal axon targeting in Drosophila. Cell 128, 961–975 (2007)

  14. 14.

    et al. The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth. Nature 522, 482–486 (2015). 10.1038/nature14298

  15. 15.

    , & Loss of PI3K blocks cell-cycle progression in a Drosophila tumor model. Oncogene 30, 4067–4074 (2011)

  16. 16.

    , & Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila. Curr. Biol. 16, 1139–1146 (2006)

  17. 17.

    et al. Oncogenic Ras diverts a host TNF tumor suppressor activity into tumor promoter. Dev. Cell 18, 999–1011 (2010)

  18. 18.

    et al. Interplay among Drosophila transcription factors Ets21c, Fos and Ftz-F1 drives JNK-mediated tumor malignancy. Dis. Model. Mech. 8, 1279–1293 (2015)

  19. 19.

    , & Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion. Nature 463, 545–548 (2010)

  20. 20.

    , & CoinFLP: a system for efficient mosaic screening and for visualizing clonal boundaries in Drosophila. Development 142, 597–606 (2015)

  21. 21.

    & Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature 461, 537–541 (2009)

  22. 22.

    et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536, 479–483 (2016)

  23. 23.

    , , & Nutrient restriction enhances the proliferative potential of cells lacking the tumor suppressor PTEN in mitotic tissues. eLife 2, e00380 (2013)

  24. 24.

    & Studying tumor growth in Drosophila using the tissue allograft method. Nat. Protocols 10, 1525–1534 (2015)

  25. 25.

    The role for autophagy in cancer. J. Clin. Invest. 125, 42–46 (2015)

  26. 26.

    , , & Domains controlling cell polarity and proliferation in the Drosophila tumor suppressor Scribble. J. Cell Biol. 167, 1137–1146 (2004)

  27. 27.

    , , , & Intrinsic tumor suppression and epithelial maintenance by endocytic activation of Eiger/TNF signaling in Drosophila. Dev. Cell 16, 458–465 (2009)

  28. 28.

    et al. Elimination of oncogenic neighbors by JNK-mediated engulfment in Drosophila. Dev. Cell 20, 315–328 (2011)

  29. 29.

    & An Atg1/Atg13 complex with multiple roles in TOR-mediated autophagy regulation. Mol. Biol. Cell 20, 2004–2014 (2009)

  30. 30.

    et al. Imp-L2, a putative homolog of vertebrate IGF-binding protein 7, counteracts insulin signaling in Drosophila and is essential for starvation resistance. J. Biol. 7, 10 (2008)

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Acknowledgements

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.

Affiliations

  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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Contributions

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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DOI

https://doi.org/10.1038/nature20815

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