Critical role for arginase 2 in obesity-associated pancreatic cancer

Tamara Zaytouni, Pei-Yun Tsai, Daniel S. Hitchcock, Cory D. DuBois, Elizaveta Freinkman, Lin Lin, Vicente Morales-Oyarvide, Patrick J. Lenehan, Brian M. Wolpin, Mari Mino-Kenudson, Eduardo M. Torres, Nicholas Stylopoulos, Clary B. Clish and Nada Y. Kalaany ()
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Tamara Zaytouni: Boston Children’s Hospital
Pei-Yun Tsai: Boston Children’s Hospital
Daniel S. Hitchcock: Broad Institute of Harvard and MIT
Cory D. DuBois: Boston Children’s Hospital
Elizaveta Freinkman: Whitehead Institute for Biomedical Research
Lin Lin: Harvard Medical School
Vicente Morales-Oyarvide: Harvard Medical School
Patrick J. Lenehan: Boston Children’s Hospital
Brian M. Wolpin: Harvard Medical School
Mari Mino-Kenudson: Massachusetts General Hospital and Harvard Medical School
Eduardo M. Torres: University of Massachusetts Medical School
Nicholas Stylopoulos: Boston Children’s Hospital
Clary B. Clish: Broad Institute of Harvard and MIT
Nada Y. Kalaany: Boston Children’s Hospital

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Despite recent identification of metabolic alterations in this lethal malignancy, the metabolic dependencies of obesity-associated PDA remain unknown. Here we show that obesity-driven PDA exhibits accelerated growth and a striking transcriptional enrichment for pathways regulating nitrogen metabolism. We find that the mitochondrial form of arginase (ARG2), which hydrolyzes arginine into ornithine and urea, is induced upon obesity, and silencing or loss of ARG2 markedly suppresses PDA. In vivo infusion of 15N-glutamine in obese mouse models of PDA demonstrates enhanced nitrogen flux into the urea cycle and infusion of 15N-arginine shows that Arg2 loss causes significant ammonia accumulation that results from the shunting of arginine catabolism into alternative nitrogen repositories. Furthermore, analysis of PDA patient tumors indicates that ARG2 levels correlate with body mass index (BMI). The specific dependency of PDA on ARG2 rather than the principal hepatic enzyme ARG1 opens a therapeutic window for obesity-associated pancreatic cancer.

Date: 2017
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DOI: 10.1038/s41467-017-00331-y

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