Autophagy maintains tumor growth through circulating arginine

Autophagy captures intracellular components and delivers them to lysosomes where they are degraded and recycled to sustain metabolism and to enable survival in starvation(1–5). Acute, whole-body deletion of the essential autophagy gene Atg7 in adult mice causes a systemic metabolic defect manifested by starvation intolerance and gradual loss of white adipose tissue (WAT), 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 tumors in autochthonous cancer models(6,7). Acute, systemic deletion of Atg7 or acute, systemic expression of a dominant-negative ATG4b in mice induces greater regression of Kras-driven cancers than tumor-specific autophagy deletion, suggesting a role for host autophagy in promoting tumor growth(1,8). Here we show that host-specific Atg7 deletion impairs growth of multiple different allografted tumors, although not all tumor lines were sensitive to host autophagy status. Host autophagy loss was associated with reduction in circulating arginine and the sensitive tumor cells lines were arginine auxotrophs due to lack of expression of the enzyme argininosuccinate synthase (ASS1). 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 degradation of serum arginine to ornithine. ARG1 is predominantly expressed in liver and can be released from hepatocytes into the circulation. Liver-specific Atg7 deletion produced circulating ARG1, and reduced serum arginine and tumor growth. Deletion of Atg5 in the host similarly regulated circulating arginine and tumorigenesis, demonstrating specificity to autophagy function. Dietary supplementation of Atg7-deficient hosts with arginine partially restored circulating arginine levels and tumor growth. Thus, defective host autophagy leads to release of ARG1 from liver and degradation of circulating arginine essential for tumor growth, identifying a novel metabolic vulnerability of cancer.