Newswise — New Brunswick, N.J. – November 14, 2018 – Tumors require nutrients to grow and survive, thus therapeutic approaches to cut off the tumor food supply are important for treating cancer. Autophagy, a normal cellular process in which intracellular components are recycled to provide nutrients to sustain survival during times of stress, is known to facilitate tumor growth, survival, and malignancy. Research from investigators at Rutgers Cancer Institute of New Jersey shows that autophagy in normal tissues as well as the tumor cells themselves also promotes tumor growth. Autophagy prevents the liver from releasing the enzyme arginase, which degrades circulating arginine that is essential for tumor growth. Thus, autophagy maintains an important tumor nutrient, arginine, in the blood supply, identifying a metabolic vulnerability of cancer.
Rutgers Cancer Institute of New Jersey Deputy Director, Chief Scientific Officer, and Associate Director for Basic Science Eileen White, PhD, who is a distinguished professor of molecular biology and biochemistry in the School of Arts and Sciences at Rutgers University; and Laura Poillet Perez, PhD, a researcher in the White Laboratory, published these findings in the November 14 online edition of Nature (DOI: 10.1038/s41586-018-0697-7). They share more about the work.
Q: How did you discover that autophagy in normal tissues promotes tumor growth?
A: A graduate student in the White Laboratory, Gizem Karsli-Uzunbas, previously showed that loss of autophagy throughout mice had more anti-tumor activity than loss of autophagy only in tumors. This suggested for the first time that autophagy in normal tissues as well as tumors might also contribute to tumor growth (Karsli-Uzunbas, et al., Cancer Discovery, August 2014). Karsli-Uzunbas also found that loss of autophagy in mice caused intolerance to fasting and reduced levels of the amino acid arginine in the circulating blood supply, indicating a role for autophagy in sustaining whole body metabolism. As tumor nutrients come from food metabolized by normal tissues in the body that are predominantly delivered by the circulating blood supply, this suggested that autophagy in normal tissues may provide critical circulating nutrients, possibly arginine, essential for tumor growth. Dr. ‘Jessie’ Yanxiang Guo in the White Laboratory tested this hypothesis and found that non-small cell lung cancer grew poorly in autophagy-deficient compared to autophagy-competent mice. Supported by a New Jersey Commission on Cancer Research fellowship, Dr. Poillet Perez came to the White Laboratory to test the novel hypothesis that autophagy maintains circulating arginine essential for tumor growth.
Q: How important is arginine for tumor growth?
A: Arginine is thought to be an important tumor nutrient as it is required to activate the master regulator of their growth, mTOR. Tumors are also well known to shut off synthesis of arginine to favor other biosynthetic pathways, so they require an external source of arginine. Poillet Perez tested tumor cell lines for arginine dependence and confirmed that they could not grow without it. Thus, the low level of circulating arginine in autophagy-deficient mice could explain why tumor growth is impaired.
Q: Why does loss of autophagy reduce circulating arginine?
A: To identify the mechanism responsible for low circulating arginine in autophagy-deficient mice Poillet Perez analyzed the proteins present in the serum of autophagy-proficient and -deficient mice using mass spectrometry proteomics. She surprisingly discovered the arginine degrading enzyme arginase in the serum with loss of autophagy. In collaboration with the laboratory of Dr. Joshua D. Rabinowitz at Princeton University, and using novel isotope tracing and mass spectroscopy technology to measure metabolism in vivo (Hui et al., Nature, October 2017), she went on to demonstrate that this serum arginase was responsible for degrading circulating arginine in mice deficient for autophagy. Arginase can be released from liver hepatocytes under stress, and Poillet Perez determined that loss of autophagy specifically in the liver was responsible for the release of arginase into the circulation and for the degradation of arginine. Moreover, dietary supplementation of autophagy-deficient mice with arginine partially restored circulating arginine and tumor growth. In summary, autophagy in the liver prevents the release of arginase and the degradation of circulating arginine, which is important for the growth of arginine-dependent tumors.
Q: Why is the discovery of regulation of circulating arginine by autophagy important?
A: Many tumors are dependent on arginine for growth and inhibition of autophagy represents a means to release arginase from the liver and deplete circulating arginine to inhibit tumor growth. Cutting off the supply of essential tumor nutrients is an important therapeutic approach for cancer therapy that remains to be further exploited. For example, degradation of the amino acid asparagine with asparaginase is an effective therapy for acute lymphoblastic leukemia. Similarly, the use of arginase to treat arginine-dependent tumors, like those described here, should also be explored further.
The work was supported by funding from the National Institutes of Health (R01 CA130893, R01CA193970, White; R01 CA163591, White, Rabinowitz; K22CA190521, Guo; R50CA211437, Lu; R01CA193970, Mehnert; P30CA072720 Rutgers Cancer Institute Cancer Center Support Grant; and S100D016400, Rutgers Biological Mass Spectrometry Facility) and the V Foundation for Cancer Research (Mehnert). Poillet-Perez received support from a postdoctoral fellowship from the New Jersey Commission on Cancer Research. Information on other support and author disclosures can be found at: DOI: 10.1038/s41586-018-0697-7.