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Microenvironmental autophagy promotes tumour growth


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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Figure 1: RasV12scrib−/− tumours induce NAA.
Figure 2: Local NAA is required for tumour growth and invasion.
Figure 3: RasV12 scrib−/− tumours produce ROS and induce NAA downstream of Egr/TNF, JNK, Sd/Yki and Upd cytokines.
Figure 4: Malignant tumours are dependent on amino acid import and host 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.

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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.

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Correspondence to Tor Erik Rusten.

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The authors declare no competing financial interests.

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

Extended data figures and tables

Extended Data Figure 1 NAA is induced in the wing disc and ChAtg8a signal derives from autophagic structures.

a, Representative confocal images of wing imaginal discs of ChAtg8a-animals carrying RasV12 scrib−/− tumours are shown. n = 17 (RasV12ctrl) and n = 19 (RasV12scrib−/−) discs from three independent experiments. b, Quantification of relative ChAtg8a intensities inside and outside clones of indicated genotypes from single confocal sections. Values represent mean and s.e.m. of three independent pooled experiments. n = 24 discs (RasV12ctrl), n = 20 discs (RasV12scrib−/−) ***P < 0.0001 from unpaired two-tailed t-test. c, Transmission electron microscopy, confocal and overlay images correlating fluorescent puncta with organelles at the ultrastructural level (insets are shown enlarged). ChAtg8a-positive areas correlate with autophagosomes and autolysosomes (1–3) and apoptotic cells with autolysosomal profiles (4). Scale bars, 50 μm (a) and 10 μm (c).

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Extended Data Figure 2 RasV12 scrib−/− tumours induce systemic autophagy in distal tissues and their invasive properties are reduced by pharmacological treatment.

a, Representative confocal images of muscles in transgenic ChAtg8a larvae used to grade the strength of autophagy induction in the presence of RasV12scrib−/− tumours in muscle, gut and adipose tissues at day 5 after egg lay. Data are mean ± s.e.m. from three independent pooled experiments. RasV12ctrl, n = 11 animals (muscles and fat body) or n = 9 animals (gut); RasV12scrib−/−, n = 7 animals (muscles, gut, fatbody). Scale bars, 50 μm. b, Representative images of VNCs used to grade tumour invasion severity upon chloroquine treatment at day 10 after egg-lay White arrow indicates weakly visible GFP-positive invading tumour tissue. Quantification is based on three independent pooled experiments. n = 65(untreated) or n = 93 (chloroquine). ***P = 0.0004 (muscles), ***P < 0.0001 (gut and fatbody) from unpaired two tailed t-test (a). **P = 0.0021 from chi-squared test (b).

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Extended Data Figure 3 Generation and characterization of an atg14 allele.

a, Cartoon depicting the genomic location of the atg14 gene and the 1,191-bp lesion created by P-element-induced imprecise excision (red). The atg14Δ5.2 null allele lacks the ATG start site and approximately two-thirds of the coding region, leading to pupal lethality. The genomic BAC rescue construct, CH322-175F03 covers the atg14 locus and its genomic insertion, g-atg14, rescues atg14Δ5.2 lethality. b, c, EADs bearing GFP-labelled atg14−/− clones (b) or atg14−/− clones in animals carrying a genomic atg14 (g-atg14) rescue construct (c), immunostained with anti-Ref(2)P antibody. Ref(2)P accumulates in cells deficient for autophagy. Images are representative of more than 20 discs for each genotype. df, EAD and adult eye morphology from animals with GFP-labelled control (e, f), atg13−/− (e) or atg14−/− (f) clones. g, Graph depicting volumes of control, atg13−/− and atg14−/− GFP-positive clones in relation to the volume of the total disc. Values depict mean ± s.e.m. of two independent pooled experiments. ctrl, n = 11 discs; atg13−/−, n = 7 discs; atg14−/−, n = 11 discs. *P ≤ 0.05, **P ≤ 0.01 from one-way ANOVA with Dunnett’s correction. Scale bars, 50 μm (bf).

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Extended Data Figure 4 Verification of reverse MARCM clonal technique for atg13 and atg14.

a, Cartoon depicting the genetic basis of the reverse MARCM clonal technique to induce labelled tumour cells confronted with autophagy-deficient neighbours. Experimental animals are heterozygous for atg13 and the tumour suppressor scrib on homologous sister chromatid arms. Mitotic (G2 phase) site-specific recombination at FLP recombination target sites (FRT) is induced between sister chromatids by transient tissue-specific expression of the dsDNA processing enzyme flipase. Severed chromosome arms can be stoichiometrically re-annealed with the sister chromatid, leading to simultaneous generation of cells carrying either two copies of scrib or atg13 loss-of-function alleles. Upon mitotic recombination, scrib−/− mutant cells simultaneously express GFP and oncogenic RasV12 under the control of an upstream activating sequence (UAS), driven by tissue-specific expression of the GAL4 yeast transcription factor. Non-recombined cells and atg13−/− cells do not express GFP or RasV12 as GAL4 activity is repressed by the presence of the yeast GAL4 repressor GAL80. b, c, Confocal images showing eye antennal discs with GFP-labelled control clones and reverse MARCM atg13−/− (b) or atg14−/− (c) clones detected by immunolabelling against the accumulating autophagy cargo protein Ref(2)P. Images are representative of more than 25 discs for each genotype. Scale bars, 50 μm (b, c).

Extended Data Figure 5 Local autophagy is required for tumour growth.

a, Invasion grading of indicated genotypes at day 8. n = 66 (RasV12scrib−/−//+), n = 55 (RasV12atg13−/−, scrib−/−//+), n = 92 (RasV12scrib−/−//atg13−/−), n = 114 (RasV12atg13−/−scrib−/−//atg13−/−), n = 59 (g-atg13RasV12scrib−/−//atg13−/−), n = 91 (g-atg13 RasV12atg13−/−scrib−/−//atg13−/−) from 3 independent pooled experiments. be, Cartoon depicting cephalic complex with brain lobes (BL), EADs and VNC and epifluorescent images of tumour growth and invasion into VNC at day 8 (b, c) and day 10 (d, e). Lack of tumour growth and invasion of RasV12scrib−/− tumours in atg13−/− mutant animals is restored by one copy of a genomic atg13 rescue transgene at day 8, and more prominently at day 10. f, Quantification of tumour volumes at day 10. Values depict mean ± s.e.m. of two pooled experiments. n = 2 (RasV12atg13−/− scrib−/−//atg13−/−), n = 20 (g-atg13RasV12atg13−/−scrib−/−//atg13−/−). g, Confocal analysis of ey3.5-atg13-GFP expression pattern. Image is representative of eight discs from two independent experiments. h, Rescue of Ref(2)P accumulation in the eye-part of the EAD (blue arrow) of ey3.5-atg13 RasV12atg13−/−scrib−/−//atg13−/− animals, where the ey3.5-atg13 rescue construct is expressed, compared to the antennal part (yellow arrow). Image is representative of nine discs from two independent experiments. Scale bars, 50 μm (g, h). **P = 0.0086, ***P < 0.0001, ns, not significant by chi-squared test(a); *P = 0.019 by unpaired two-tailed t-test(f).

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Extended Data Figure 6 Inhibition of autophagy reduces tumour proliferation, but does not increase cell death.

ae, Overlayed flow cytometry histograms of dissociated EAD cells with cell-cycle phasing of tumour cell population (GFP+, green) and microenvironmental cell population (GFP-, brown). 10,000 GFP-positive cells per genotype were analysed. Histograms are representative of three independent experiments. In contrast to cells from RasV12 tumours (a), RasV12scrib−/− tumours (b) display increased cell cycle progression whereas RasV12atg13−/−scrib−/− tumours (c), RasV12scrib−/− tumour cells confronted with atg13−/− cells in the microenvironment (d) or in atg13 null animals (e) are suppressed. f, Percentage of phosphorylated histone 3-positive mitotic cells within clones normalized to percentage of GFP-positive (tumour) tissue area quantified from single confocal image sections. Values depict mean ± s.e.m from three independent pooled experiments. n = 12 (RasV12ctrl//+, RasV12scrib−/−//+ and RasV12atg13−/−scrib−/−//atg13−/−); n = 15 (RasV12atg13−/−scrib−/−//+); or n = 10 discs (RasV12scrib−/−//atg13−/−)***P ≤ 0.001; ns, not significant from one-way ANOVA with Dunnett’s correction. gk, Confocal images of tumorous discs with phosphorylated histone 3-labelled mitotic cells. In contrast to cells from RasV12 tumours (a), RasV12scrib−/− tumours (h) and RasV12atg13−/−scrib−/− tumours (i) display increased phosphorylated histone 3. RasV12scrib−/− tumour cells facing atg13−/− cells in the microenvironment (j) or in atg13 null animals (k), on the other hand, display fewer phosphorylated histone 3-positive foci. White arrow indicates phosphorylated histone 3-positive cells in the microenvironment population. Images are representative of more than 20 discs per genotype from three independent experiments. lp, Confocal images of EAD of the indicated genotypes with EdU-labelled S-phase cells. White arrow indicates EdU-positive cells in the microenvironment population. Images are representative of six or more discs from two independent experiments. qu, Cleaved caspase 3 staining (white arrows) is low in RasV12 tumours (q), prominent within the tumour cell population in discs carrying RasV12scrib−/− tumours (r), RasV12atg13−/−scrib−/− tumours(s), RasV12scrib−/− tumour cells confronted with atg13−/− cells (t) and RasV12scrib−/− tumours in atg13-deficient animals (u).

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Extended Data Figure 7 NAA responses.

a, Systemic autophagy grading upon tumour intrinsic inhibition of JNK signalling in the EAD. Values depict mean ± s.e.m. of three independent pooled experiments. n = 7 (RasV12scrib−/−) or 11 (bskDNRasV12scrib−/−) animals. bj, Representative confocal images, quantified in Extended Data Fig. 7k–m. NAA is downstream of Fos and Ets21c transcription factor activity (b). Expression of bskDN suppresses NAA (c). Clonal overexpression of yki is sufficient to trigger autophagy in neighbouring cells (d). Knockdown of yki suppresses NAA (e). Reduction of tumour growth by disrupted PI3K-I signalling does not affect NAA induction (f). ImpL2 is neither sufficient nor necessary for NAA (g, h). Upd3 cooperates with RasV12 for NAA induction (i). Removal of JAK/STAT signalling in neighbouring tissue does not suppress NAA (j). Quantification of relative 3 × ChAtg8a-intensities of indicated genotypes (k). Data are mean ± s.e.m. from three independent pooled experiments. n = 38 (RasV12scrib−/−), n = 24 (RasV12egr−/−scrib−/−), n = 18 (RasV12scrib−/−, bskDN), n = 17 (RasV12scrib−/−kay−/−), n = 29 (RasV12ets21cRNAiscrib−/−fosRNAi), n = 34 (RasV12domeDNscrib−/−), n = 5 (RasV12upd1ctrl) or n = 9 (ykiactctrl) discs. l, Relative 3× ChAtg8a intensities of indicated genotypes. Data are mean ± s.e.m. from three independent pooled experiments, n = 15 (RasV12dlg1RNAi),n = 11 (RasV12 dlg1RNAisdRNAi),n = 2 (RasV12dlg1RNAibskDN), n = 10 (RasV12dlg1RNAiykiRNAi), n = 7 (RasV12dlg1RNAiImpL2RNAi) or n = 5 (RasV12 dlg1RNAidp110DN) discs. m, Quantification of relative ChAtg8a intensities of indicated genotypes. Data are mean ± s.e.m. of three independent pooled experiments. n = 24 (RasV12ctrl), n = 20 (RasV12scrib−/−), n = 9 (ImpL2RasV12ctrl), n = 12 (upd3RasV12ctrl) or 15 (RasV12scrib−/−//stat−/−) discs. Scale bars, 50 μm (bj). *P = 0.0127; ns, not significant by unpaired two-tailed t-test (a). *P ≤ 0.05, **P ≤ 0.01, ***P < 0.0001 by one-way ANOVA with Dunnett’s correction (km).

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Extended Data Figure 8 Transformed cells display increased mitochondrial mass, ROS, glucose uptake and reduced reserve respiratory capacity.

a, Stitched electron microscopy overview image of sectioned RasV12 scrib−/− disc. Blue dots label nuclei of tumour cells, yellow dots those of neighbour cells. Light blue lines demarcate clone boundaries. Model to the upper right visualizing clone boundaries was reconstructed based on consecutive electron microscopy sections. Inset (black outline) is shown in a’, containing two more insets from either side of the clone boundary (blue and yellow, a’’ and a’’’, respectively). Red asterisks indicate damaged mitochondria, green asterisks healthy mitochondria. White arrows indicate breached mitochondrial membrane. b, Table summarizing quantification of mitochondrial mass and health in two independent areas on electron microscopy sections within and outside RasV12scrib−/− clone boundaries. c, Confocal images of EADs carrying RasV12scrib−/− tumours labelled with ATP5a, showing increased mitochondrial mass. Images are representative of 6 (RasV12ctrl) or 11 (RasV12scrib−/−) discs from three independent experiments. Scale bars, 50 μm. d, Representative MitoTracker intensity profile and quantification of GFP-positive and GFP-negative cells from dissociated RasV12scrib−/−//+ EADs. Data are mean ± s.e.m. from three independent experiments. e, Representative MitoSOX fluorescence intensity profile and quantification of GFP-positive and GFP-negative cells from dissociated RasV12scrib−/−//+ EAD. Data are mean ± s.e.m. from three independent experiments. f, Seahorse-derived measurements of ratios between maximal and basal respiration capacity in tumour cells (RasV12scrib−/−) and the microenvironment compared to wild-type cells. Data are mean ± s.e.m. from three (wild type), four (RasV12scrib−/−) and two (microenvironment) independent wells and are representative of three independent experiments. g, h, Knockdown of ND75 in the dorsal domain of the wing imaginal disc triggers NAA. Images are representative of n = 9 discs (ctrl and ND75RNAi) from three independent experiments. i, DHE staining of eye-antennal disc with Ykiact expressing cells that show tumorous growth and outcompete neighbouring wild type cells. n = 6 discs from two independent experiments. j, Ykiact −induced cell competition and growth does not change when cells are confronted with atg13−/−-deficient microenvironment. Graph shows GFP-positive tissue volumes normalized to disc volumes. Data are mean ± s.e.m. from three independent pooled experiments, n = 17 (ykiactctrl//+) or n = 12 (ykiactctrl//atg13−/−) discs. k, l, RasV12scrib−/− tumours display enhanced uptake of glucose. Images are representative of n = 17 (RasV12ctrl) or 6 (RasV12scrib−/−) discs from three independent experiments. Scale bars, 50 μm (c, gh, i, kl). ***P = 0.0017 (d) and *P = 0.039 from one-sample t-test (e). *P < 0.05, from one-way ANOVA with Dunnett’s correction (f). (j) ns, not significant (P = 0.137) from two-tailed unpaired t-test.

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Extended Data Figure 9 Host autophagy requirement for tumour growth.

a, Quantification of tumour volumes upon slif knockdown at day 6. Data are mean ± s.e.m. from three independent pooled experiments. n = 15 (RasV12dlg1RNAi) or 13 (RasV12dlg1RNAi slifanti) animals. b, Tumour growth of RasV12scrib−/− allografted tissue at 2 and 10 days post injection (DPI). c, Western blot analysis of autophagic flux in ovaries of host flies carrying RasV12scrib−/− transplants for 5 days. Data are mean ± s.e.m. of three independent experiments. d, SAR405 reduces allograft tumour volumes in host flies after 8 days. Data are mean ± s.e.m. of three independent pooled experiments. n = 36 (DMSO) or n = 50 (SAR405) animals. e, Day 10 RasV12 scrib−/− tumour allograft volumes from atg14Δ5.2/atg14EY14568 hosts with or without a genomic atg14 rescue transgene. Data are mean ± s.e.m. of three independent pooled experiments. n = 32 (g-atg14; atg14Δ5.2/atg14EY14568 hosts) or n = 46 (atg14Δ5.2/atg14EY14568 hosts) animals. f, Non-growing RasV12atg13−/−scrib−/−//atg13−/− tumours regrow more effectively when allografted into control hosts than into atg8-mutant hosts. Data are mean ± s.e.m. of three independent pooled experiments. n = 41 (ctrl hosts) or n = 23 (Δatg8a hosts) animals. ***P < 0.0001 from unpaired two-tailed t-test (a); ***P = 0.0073 from one-sample t-test (c); **P = 0.0036 (d); ***P < 0.0001 (e); and (f) ***P < 0.0005 from unpaired two-tailed t-test. ns, not significant.

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Katheder, N., Khezri, R., O’Farrell, F. et al. Microenvironmental autophagy promotes tumour growth. Nature 541, 417–420 (2017).

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