Author
Listed:
- Laura Poillet-Perez
(Rutgers Cancer Institute of New Jersey)
- Xiaoqi Xie
(Rutgers Cancer Institute of New Jersey)
- Le Zhan
(Rutgers Cancer Institute of New Jersey)
- Yang Yang
(Rutgers Cancer Institute of New Jersey)
- Daniel W. Sharp
(Rutgers Cancer Institute of New Jersey)
- Zhixian Sherrie Hu
(Rutgers Cancer Institute of New Jersey)
- Xiaoyang Su
(Rutgers Cancer Institute of New Jersey
Robert Wood Johnson Medical School, Rutgers University)
- Anurag Maganti
(Rutgers Cancer Institute of New Jersey)
- Cherry Jiang
(Rutgers Cancer Institute of New Jersey)
- Wenyun Lu
(Princeton University)
- Haiyan Zheng
(Rutgers University, Robert Wood Johnson Medical School, Rutgers University)
- Marcus W. Bosenberg
(Yale University School of Medicine)
- Janice M. Mehnert
(Rutgers Cancer Institute of New Jersey
Robert Wood Johnson Medical School, Rutgers University)
- Jessie Yanxiang Guo
(Rutgers Cancer Institute of New Jersey
Robert Wood Johnson Medical School, Rutgers University
Rutgers Ernest Mario School of Pharmacy)
- Edmund Lattime
(Rutgers Cancer Institute of New Jersey
Robert Wood Johnson Medical School, Rutgers University)
- Joshua D. Rabinowitz
(Rutgers Cancer Institute of New Jersey
Princeton University)
- Eileen White
(Rutgers Cancer Institute of New Jersey
Rutgers University)
Abstract
Autophagy captures intracellular components and delivers them to lysosomes, where they are degraded and recycled to sustain metabolism and to enable survival during starvation1–5. 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.
Suggested Citation
Laura Poillet-Perez & Xiaoqi Xie & Le Zhan & Yang Yang & Daniel W. Sharp & Zhixian Sherrie Hu & Xiaoyang Su & Anurag Maganti & Cherry Jiang & Wenyun Lu & Haiyan Zheng & Marcus W. Bosenberg & Janice M., 2018.
"Autophagy maintains tumour growth through circulating arginine,"
Nature, Nature, vol. 563(7732), pages 569-573, November.
Handle:
RePEc:nat:nature:v:563:y:2018:i:7732:d:10.1038_s41586-018-0697-7
DOI: 10.1038/s41586-018-0697-7
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Cited by:
- Liping Huang & Hongwei Sun & Liangbin Sun & Keqing Shi & Yuzhe Chen & Xueqian Ren & Yuancai Ge & Danfeng Jiang & Xiaohu Liu & Wolfgang Knoll & Qingwen Zhang & Yi Wang, 2023.
"Rapid, label-free histopathological diagnosis of liver cancer based on Raman spectroscopy and deep learning,"
Nature Communications, Nature, vol. 14(1), pages 1-14, December.
- Chenglong Sun & Anqiang Wang & Yanhe Zhou & Panpan Chen & Xiangyi Wang & Jianpeng Huang & Jiamin Gao & Xiao Wang & Liebo Shu & Jiawei Lu & Wentao Dai & Zhaode Bu & Jiafu Ji & Jiuming He, 2023.
"Spatially resolved multi-omics highlights cell-specific metabolic remodeling and interactions in gastric cancer,"
Nature Communications, Nature, vol. 14(1), pages 1-14, December.
- Lucia Taraborrelli & Yasin Şenbabaoğlu & Lifen Wang & Junghyun Lim & Kerrigan Blake & Noelyn Kljavin & Sarah Gierke & Alexis Scherl & James Ziai & Erin McNamara & Mark Owyong & Shilpa Rao & Aslihan Ka, 2023.
"Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer,"
Nature Communications, Nature, vol. 14(1), pages 1-17, December.
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