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.
Extended data figures
This file contains the uncropped western blots and Supplementary Methods (a list of detailed genotypes for each figure).
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Autophagy-related gene LC3 expression in tumor and liver microenvironments significantly predicts recurrence of hepatocellular carcinoma after surgical resection
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