Autophagy Sustains Tumors by Maintaining Serum Arginine Levels

Autophagy maintains cellular homeostasis by degrading and recycling intracellular components to support the metabolic demands of proliferating cancer cells, as tumor-specific inhibition of autophagy suppresses tumor growth. Poillet-Perez and colleagues observed that host-specific inhibition of autophagy through deletion of Atg7 or Atg5 also suppressed the growth and proliferation of multiple allografted tumors. Serum metabolite profiling revealed a marked decrease in circulating arginine levels upon host autophagy loss, suggesting that host autophagy sustains tumor growth by providing tumor cells with arginine. Not every tumor model evaluated was dependent on host autophagy, but most tumors that could not synthesize arginine due to loss of argininosuccinate synthase 1 (ASS1) expression were dependent on host autophagy and the presence of circulating arginine. Circulating arginine was depleted upon loss of host autophagy due to increased serum levels of the arginine-degrading enzyme arginase 1 (ARG1), which was released from damaged liver hepatocytes into the circulation. Dietary supplementation of autophagy-deficient hosts with arginine partially restored serum arginine levels and promoted growth of arginine-auxotrophic tumors, further suggesting that sufficient circulating arginine is necessary to support tumor growth. These findings establish that host autophagy can sustain tumor growth by maintaining circulating levels of required nutrients and raise the possibility that limiting essential tumor nutrients in circulation may be an effective way to exploit metabolic vulnerabilities of tumors and suppress tumor growth.

Poillet-Perez L, Xie X, Zhan L, Yang Y, Sharp DW, Hu ZS, et al. Autophagy maintains tumour growth through circulating arginine. Nature 2018;563:569–73.

• ©2019 American Association for Cancer Research.