Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma

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Abstract

Current therapies for sarcomas are often inadequate. This study sought to identify actionable gene targets by selective targeting of the molecular networks that support sarcoma cell proliferation. Silencing of asparagine synthetase (ASNS), an amidotransferase that converts aspartate into asparagine, produced the strongest inhibitory effect on sarcoma growth in a functional genomic screen of mouse sarcomas generated by oncogenic Kras and Cdkn2a. ASNS silencing in mouse and human sarcoma cell lines reduced the percentage of S phase cells and impeded new polypeptide synthesis. These effects of ASNS silencing were reversed by exogenous supplementation with asparagine. Also, asparagine depletion via the ASNS inhibitor amino sulfoximine 5 (AS5) or asparaginase inhibited mouse and human sarcoma growth in vitro, and genetic silencing of ASNS in mouse sarcoma cells combined with depletion of plasma asparagine inhibited tumor growth in vivo. Asparagine reliance of sarcoma cells may represent a metabolic vulnerability with potential anti-sarcoma therapeutic value.

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Author details

Simone Hettmer

Pediatric Hematology/ Oncology, University Medical Center Freiburg, Freiburg, Germany

Competing interests
No competing interests declared.
Anna C Schinzel

Medical Oncology, Dana-Farber Cancer Institute, Boston, United States

Competing interests
No competing interests declared.
Daria Tchessalova

Neuroscience Graduate Program, University of Michigan, Ann Arbor, United States

Competing interests
No competing interests declared.
Michaela Schneider

Pediatric hematology/ oncology, University Medical Center Freiburg, Freiburg, Germany

Competing interests
No competing interests declared.
Christina L. Parker

Molecular Pharmaceutics, University of North Carolina, Chapel Hill, United States

Competing interests
No competing interests declared.
Roderick Bronson

Harvard Medical School, Harvard University, Boston, United States

Competing interests
No competing interests declared.
Nigel G.J. Richards

Chemistry & Chemical Biology, Indiana University - Purdue University Indianapolis, Indianapolis, United States

Competing interests
No competing interests declared.
William Hahn

Dana Farber Cancer Institute, *, United States

Competing interests
No competing interests declared.
Amy J Wagers

Harvard Stem Cell Institute, Harvard University, United States

For correspondence
amy.wagers@joslin.harvard.edu

Competing interests
Amy J Wagers, Reviewing editor, eLife.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the Joslin Diabetes Center. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Joslin Diabetes Center. All surgery was performed under tribromoethanol or isoflurane anesthesia, and every effort was made to minimize suffering.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.