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Autophagy maintains tumour growth through circulating arginine

An Author Correction to this article was published on 06 December 2018

This article has been updated

Abstract

Autophagy captures intracellular components and delivers them to lysosomes, where they are degraded and recycled to sustain metabolism and to enable survival during starvation1,2,3,4,5. Acute, whole-body deletion of the essential autophagy gene Atg7 in adult mice causes a systemic metabolic defect that manifests as starvation intolerance and gradual loss of white adipose tissue, liver glycogen and muscle mass1. Cancer cells also benefit from autophagy. Deletion of essential autophagy genes impairs the metabolism, proliferation, survival and malignancy of spontaneous tumours in models of autochthonous cancer6,7. Acute, systemic deletion of Atg7 or acute, systemic expression of a dominant-negative ATG4b in mice induces greater regression of KRAS-driven cancers than does tumour-specific autophagy deletion, which suggests that host autophagy promotes tumour growth1,8. Here we show that host-specific deletion of Atg7 impairs the growth of multiple allografted tumours, although not all tumour lines were sensitive to host autophagy status. Loss of autophagy in the host was associated with a reduction in circulating arginine, and the sensitive tumour cell lines were arginine auxotrophs owing to the lack of expression of the enzyme argininosuccinate synthase 1. Serum proteomic analysis identified the arginine-degrading enzyme arginase I (ARG1) in the circulation of Atg7-deficient hosts, and in vivo arginine metabolic tracing demonstrated that serum arginine was degraded to ornithine. ARG1 is predominantly expressed in the liver and can be released from hepatocytes into the circulation. Liver-specific deletion of Atg7 produced circulating ARG1, and reduced both serum arginine and tumour growth. Deletion of Atg5 in the host similarly regulated circulating arginine and suppressed tumorigenesis, which demonstrates that this phenotype is specific to autophagy function rather than to deletion of Atg7. Dietary supplementation of Atg7-deficient hosts with arginine partially restored levels of circulating arginine and tumour growth. Thus, defective autophagy in the host leads to the release of ARG1 from the liver and the degradation of circulating arginine, which is essential for tumour growth; this identifies a metabolic vulnerability of cancer.

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Fig. 1: Host autophagy promotes growth of arginine auxotrophic tumours.
Fig. 2: Levels of ARG1 in serum increase in Atg7Δ/Δ hosts and deplete circulating arginine.
Fig. 3: Atg7 deletion in liver increases serum ARG1, and decreases serum arginine and tumour growth.
Fig. 4: Dietary arginine supplementation rescues tumour growth in Atg7Δ/Δ hosts.

Data availability

All data are available from the authors upon reasonable request. Source Data for Figs. 1d, 2b, 3d are provided with the paper. The raw mass spectrometry data have been deposited in the MassIVE repository, entry MSV000082879.

Change history

  • 06 December 2018

    In this Letter, ‘released’ should have been ‘regulated’ in the sentence starting: ‘Deletion of Atg5 in the host similarly regulated circulating arginine and suppressed tumorigenesis...’ This has been corrected online.

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Acknowledgements

This work was supported by National Institutes of Health grants: R01CA130893, R01CA188096 (to E.W.), R01CA163591 (to E.W. and J.D.R.), K22CA190521 (to J.Y.G.), R50CA211437 (to W.L.), R01CA193970 and the V Foundation for Cancer Research (to J.M.M.). L.P.-P. received support from a postdoctoral fellowship from the New Jersey Commission for Cancer Research (DHFS16PPC034). We thank the Rutgers-New Brunswick/Robert Wood Johnson Medical School Biological Mass Spectrometry Facility (S10OD016400) for mass spectrometry analysis, and the Biospecimen Repository and Histopathology Service, Metabolomics Service, Flow Cytometry and Biometrics Shared Resources (D. Moore performed the statistical analysis of the proteomics data) of Rutgers Cancer Institute of New Jersey (P30CA072720).

Reviewer information

Nature thanks R. DeBerardinis and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Affiliations

Authors

Contributions

L.P.-P. performed the majority of the experimental work and wrote the manuscript. L.Z. performed surgery and infusion with labelled arginine. Y.Y. developed the methods and provided the mice required for generating Atg5Δ/Δ and hosts with liver-specific deletion of Atg5. A.M. and C.J. assisted with in vitro experiments. X.X. and J.Y.G. performed some of the tumour growth experiments. J.M.M. provided melanoma expertise. D.W.S. and E.L. assisted with CD4 and CD8 depletion. Z.S.H. assisted with mouse husbandry. H.Z. performed proteomics processing and analysis. X.S., W.L. and J.D.R. performed metabolomics processing and analysis. M.W.B. provided YUMM 1.1, 1.3, 1.7 and 1.9 melanoma cells. E.W. is the leading principal investigator who conceived the project, supervised research and edited the paper.

Corresponding author

Correspondence to Eileen White.

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E.W. is co-founder of Vescor Therapeutics. The other authors declare no competing interests.

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Extended data figures and tables

Extended Data Fig. 1 Host autophagy promotes growth of different tumour cell types.

a, c, e, Comparison of tumour weight between Atg7+/+ (n = 5) and Atg7Δ/Δ (a, n = 4; c, n = 5; e, n = 4) hosts after injection of 1.3 (a), MB49 (c) or 71.8 (e) cells. Data are mean ± s.e.m. *P < 0.05, **P < 0.01. b, d, f, Immunohistochemistry quantification of Ki-67+ and active caspase-3+ cells in tumours from Atg7+/+ and Atg7Δ/Δ hosts. Data are mean ± s.e.m. *P < 0.05, ***P < 0.001, ****P < 0.0001.

Source data

Extended Data Fig. 2 Immune response is not involved in decreased tumour growth observed in Atg7Δ/Δ hosts.

ac, Comparison of tumour weight between Atg7+/+ (n = 5) and Atg7Δ/Δ (a, n = 5; c, n = 6) hosts after injection of 1.7 (a) or 1.9 (c) cells. Data are mean ± s.e.m. b, d, Immunohistochemistry quantification of Ki-67+ and active caspase-3+ in 1.7 (b) and 1.9 (d) tumours from Atg7+/+ and Atg7Δ/Δ hosts. Data are mean ± s.e.m. e, Representative immunohistochemistry images and quantification of CD3+, CD4+ and CD8+ cells in tumours from Atg7+/+ and Atg7Δ/Δ hosts. Data are mean ± s.e.m. f, Comparison of tumour volume and weight between Atg7+/+ (n = 10), Atg7+/+ + CD4 and CD8 antibody depletion (n = 15), Atg7Δ/Δ (n = 7) and Atg7Δ/Δ + CD4 and CD8 antibody depletion (n = 8) hosts. Data are mean ± s.e.m. *P < 0.05, ****P < 0.0001. g, Fold change in immune components between Atg7+/+ and Atg7Δ/Δ, with or without antibody depletion (n = 5 each). Treg, T regulatory cells; DC, dendritic cells; MDSC, myeloid-derived suppressor cells. Data are mean ± s.e.m. ***P < 0.001, ****P < 0.0001, by two-way ANOVA test.

Source data

Extended Data Fig. 3 Tumour cells are arginine auxotrophs.

a, YUMM 1.3, 71.8, MB49 and YUMM 1.7, 1.9 proliferation in vitro, in medium containing different percentages of arginine. Cell density was measured every 2 h using the IncuCyte. Data are representative of three independent experiments performed in duplicate. b, Western blotting showing expression of ASS1, ASL and OTC in kidneys and livers from Atg7+/+ and Atg7Δ/Δ hosts. *P < 0.05 compared to Atg7+/+ hosts. Data are representative of three independent experiments. Actin was used as a loading (kidney ASL and liver OTC) and processing (kidney ASS1, liver ASS1 and ASL) control. c, Western blotting showing expression of ASS1, ASL and OTC in YUMM 1.7 tumours from Atg7+/+ and Atg7Δ/Δ hosts. Data are representative of two independent experiments. Actin was used as a loading (OTC) and processing (ASS1 and ASL) control. d, Analysis of levels of nitric oxide in serum in Atg7+/+ (n = 11) and Atg7Δ/Δ (n = 9) hosts. Data are mean ± s.e.m.

Source data

Extended Data Fig. 4 Atg7 deletion increases serum arginine degradation but does not modify arginine metabolism in kidney and liver.

a, Serum 13C6-arginine and 13C5-ornithine in Atg7+/+ and Atg7Δ/Δ hosts (n = 3 each) over time. Data are mean ± s.e.m. b, Concentration (in μΜ) of arginine, citrulline and ornithine in serum from Atg7+/+ (n = 3) and Atg7Δ/Δ hosts (n = 4), after infusion with 13C615N4-arginine. c, d, Concentration (in nmol g−1) of arginine, citrulline and ornithine in kidneys (c) and livers (d) from Atg7+/+ and Atg7Δ/Δ hosts (n = 2 each) after infusion with 13C615N4-arginine. Data are mean. **P < 0.01 by two-way ANOVA test.

Source data

Extended Data Fig. 5 Liver-specific deletion of Atg7 leads to liver-cell enlargement without affecting other tissues.

ac, Western blotting showing expression of Atg7 in livers (n = 11 each) (a), brains (n = 9 and 11, respectively) (b) and kidneys (n = 10 each) (c) from Atg7+/+ hosts and hosts with liver-specific deletion of Atg7. *P < 0.05 compared to Atg7+/+ hosts. Data are representative of two independent experiments. Actin was used as a loading control. d, Representative haematoxylin and eosin tissue staining from Atg7+/+ hosts and hosts with liver-specific deletion of Atg7. Images are representative of two independent experiments. e, Analysis of levels of nitric oxide in serum, in Atg7+/+ hosts (n = 13) and hosts with liver-specific deletion of Atg7 (n = 15). Data are mean ± s.e.m. f, Comparison of serum metabolites that are significantly regulated in Atg7Δ/Δ hosts and hosts with liver-specific deletion of Atg7 (n = 17 each, P < 0.05).

Source data

Extended Data Fig. 6 Atg5 deletion increased serum ARG1, decreased serum arginine and tumour growth.

a, Experimental design to induce host mice with conditional whole-body deletion of Atg5 (Atg5Δ/Δ) and wild-type controls (Atg5+/+) with which to assess tumour growth. Ubc-creERT2/+;Atg5+/+ and Ubc-creERT2/+;Atg5flox/flox mice were injected with TAM at 8 to 10 weeks of age to delete Atg5 and create Atg5+/+ and Atg5Δ/Δ hosts. Mice were then injected subcutaneously with tumour cells and tumour growth was monitored over three weeks. b, Comparison of tumour weight between Atg5+/+ (n = 4) and Atg5Δ/Δ (n = 3) hosts. Data are mean ± s.e.m. **P < 0.01. c, Immunohistochemistry quantification of Ki-67+ and active caspase-3+ cells in tumours from Atg5+/+ and Atg5Δ/Δ hosts. Data are mean ± s.e.m. ****P < 0.0001. d, Western blotting showing expression of ARG1 in serum from Atg5+/+ (n = 3), Atg5Δ/Δ (n = 4) and Atg7Δ/Δ (n = 3) hosts. *P < 0.05 compared to Atg5+/+ hosts. Transferrin was used as a loading control. e, Levels of arginine, ornithine and citrulline in serum in Atg5+/+ (n = 4) and Atg5Δ/Δ (n = 3) hosts, obtained by LC–MS. Data are mean ± s.e.m. *P < 0.05, **P < 0.01.

Source data

Extended Data Fig. 7 Liver-specific Atg5-deleted hosts present liver-cell enlargement, increased serum ARG1 and decreased serum arginine.

a, Experimental design to induce liver-specific deletion of Atg5. Atg5flox/flox mice were injected in the tail vein with AAV–TBG–GFP or AAV–TBG–iCre at 8 to 10 weeks of age to delete Atg5 in the liver and create Atg5+/+ hosts and hosts with liver-specific deletion of Atg5, respectively. b, Western blotting showing expression of Atg5 in the livers, brains and kidneys of Atg5+/+ hosts and hosts with liver-specific deletion of Atg5 (n = 6 each). *P < 0.05 compared to Atg5+/+ hosts. Actin was used as a loading control c, Haematoxylin and eosin tissue staining from Atg5+/+ hosts and hosts with liver-specific deletion of Atg5 (n = 6 each). d, Western blotting showing expression of ARG1 in serum from Atg5+/+ hosts and hosts with liver-specific deletion of Atg5 (n = 6 each). *P < 0.05 compared to Atg5+/+ hosts. Transferrin was used as a loading control. e, Levels of arginine, ornithine and citrulline in serum in Atg5+/+ hosts and hosts with liver-specific deletion of Atg5 (n = 6 each), obtained by LC–MS. Data are mean ± s.e.m. ***P < 0.001, ****P < 0.0001.

Source data

Extended Data Fig. 8 Dietary arginine supplementation rescues YUMM 1.3 tumour growth in Atg7Δ/Δ hosts.

a, Serum arginine, ornithine and citrulline in Atg7+/+ (n = 5), Atg7+/+ + 1% arginine (n = 5), Atg7Δ/Δ (n = 6) and Atg7Δ/Δ + 1% arginine (n = 6) hosts, obtained by LC–MS. Data are mean ± s.e.m. *P < 0.05, **P < 0.01. b, Comparison of YUMM 1.3 tumour weight between Atg7+/+ and Atg7Δ/Δ (n = 5 each) hosts, with or without arginine supplementation. Data are mean ± s.e.m. **P < 0.01, ****P < 0.0001. c, Immunohistochemistry quantification of Ki-67+ and active caspase-3+ cells in tumours from Atg7+/+ and Atg7Δ/Δ hosts, with or without arginine supplementation. Data are mean ± s.e.m. **P < 0.01, ****P < 0.0001.

Source data

Supplementary information

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This file contains Supplementary Figure 1: Source data gels western blotting

Reporting Summary

Supplementary Table

This file contains Supplementary Tables 1-5. Supplementary table 1: Metabolites with significant changes in Atg7/ vs Atg7+/+ hosts. Supplementary table 2: Unchanged metabolites in Atg7/ vs Atg7+/+ hosts. Supplementary table 3: Proteins with significant changes in Atg7/ vs Atg7+/+ host. Supplementary table 4: Metabolites with significant changes in liver specific Atg7 deleted host vs Atg7 WT host. Supplementary table 5: Unchanged metabolites in liver specific Atg7 deleted host vs Atg7 WT host

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Poillet-Perez, L., Xie, X., Zhan, L. et al. Autophagy maintains tumour growth through circulating arginine. Nature 563, 569–573 (2018). https://doi.org/10.1038/s41586-018-0697-7

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Keywords

  • Liver-specific Deletion
  • Host Autophagy
  • Argininosuccinate Synthetase (ASS1)
  • Serum Arginine
  • Ornithine Transcarbamylase

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