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

  1. Simone Hettmer
  2. Anna C Schinzel
  3. Daria Tchessalova
  4. Michaela Schneider
  5. Christina L. Parker
  6. Roderick Bronson
  7. Nigel G.J. Richards
  8. William Hahn
  9. Amy J Wagers  Is a corresponding author
  1. University Medical Center Freiburg, Germany
  2. Dana-Farber Cancer Institute, United States
  3. University of Michigan, United States
  4. University of North Carolina, United States
  5. Harvard University, United States
  6. Indiana University - Purdue University Indianapolis, United States
  7. Dana Farber Cancer Institute, United States

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.

Article and author information

Author details

  1. Simone Hettmer

    Pediatric Hematology/ Oncology, University Medical Center Freiburg, Freiburg, Germany
    Competing interests
    No competing interests declared.
  2. Anna C Schinzel

    Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  3. Daria Tchessalova

    Neuroscience Graduate Program, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  4. Michaela Schneider

    Pediatric hematology/ oncology, University Medical Center Freiburg, Freiburg, Germany
    Competing interests
    No competing interests declared.
  5. Christina L. Parker

    Molecular Pharmaceutics, University of North Carolina, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  6. Roderick Bronson

    Harvard Medical School, Harvard University, Boston, United States
    Competing interests
    No competing interests declared.
  7. Nigel G.J. Richards

    Chemistry & Chemical Biology, Indiana University - Purdue University Indianapolis, Indianapolis, United States
    Competing interests
    No competing interests declared.
  8. William Hahn

    Dana Farber Cancer Institute, *, United States
    Competing interests
    No competing interests declared.
  9. 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.

Copyright

© 2015, Hettmer et al.

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.

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  1. Simone Hettmer
  2. Anna C Schinzel
  3. Daria Tchessalova
  4. Michaela Schneider
  5. Christina L. Parker
  6. Roderick Bronson
  7. Nigel G.J. Richards
  8. William Hahn
  9. Amy J Wagers
(2015)
Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma
eLife 4:e09436.
https://doi.org/10.7554/eLife.09436

Share this article

https://doi.org/10.7554/eLife.09436

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