Format

Send to

Choose Destination
Nat Commun. 2017 Aug 14;8(1):242. doi: 10.1038/s41467-017-00331-y.

Critical role for arginase 2 in obesity-associated pancreatic cancer.

Author information

1
Division of Endocrinology, Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, 02115, USA.
2
Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.
3
Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
4
Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA.
5
Metabolon Inc, Research Triangle Park, Durham, NC, 27709, USA.
6
Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA, 02215, USA.
7
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
8
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
9
Division of Endocrinology, Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, 02115, USA. Nada.Kalaany@childrens.harvard.edu.
10
Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA. Nada.Kalaany@childrens.harvard.edu.
11
Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA. Nada.Kalaany@childrens.harvard.edu.

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.Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Here the authors show that obesity induces the expression of the mitochondrial form of arginase ARG2 in PDA and that ARG2 silencing or loss results in ammonia accumulation and suppression of obesity-driven PDA tumor growth.

PMID:
28808255
PMCID:
PMC5556090
DOI:
10.1038/s41467-017-00331-y
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center