TitleAutophagy maintains tumour growth through circulating arginine.
Publication TypeJournal Article
Year of Publication2018
AuthorsPoillet-Perez, L, Xie, X, Zhan, L, Yang, Y, Sharp, DW, Hu, ZSherrie, Su, X, Maganti, A, Jiang, C, Lu, W, Zheng, H, Bosenberg, MW, Mehnert, JM, Guo, JYanxiang, Lattime, E, Rabinowitz, JD, White, E
Date Published2018 11
KeywordsAllografts, Animals, Arginase, Arginine, Autophagy, Autophagy-Related Protein 5, Autophagy-Related Protein 7, Carcinogenesis, Cell Proliferation, Dietary Supplements, Hepatocytes, Liver, Male, Mice, Neoplasm Transplantation, Neoplasms, Ornithine

Autophagy captures intracellular components and delivers them to lysosomes, where they are degraded and recycled to sustain metabolism and to enable survival during starvation. 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 mass. 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 cancer. 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 growth. 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 [corrected] 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.

Alternate JournalNature
PubMed ID30429607
PubMed Central IDPMC6287937
Grant ListR01 CA196660 / CA / NCI NIH HHS / United States
P30 CA072720 / CA / NCI NIH HHS / United States
R01 CA193970 / CA / NCI NIH HHS / United States
K22 CA190521 / CA / NCI NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States
S10 OD016400 / OD / NIH HHS / United States
R50 CA211437 / CA / NCI NIH HHS / United States
R01 CA130893 / CA / NCI NIH HHS / United States
R01 CA188096 / CA / NCI NIH HHS / United States