2. Academic Validation
  3. Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma

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

  • Elife. 2015 Oct 24;4:e09436. doi: 10.7554/eLife.09436.
Simone Hettmer 1 2 3 4 5,  Anna C Schinzel 6 7,  Daria Tchessalova 1 5,  Michaela Schneider 4,  Christina L Parker 8 9,  Roderick T Bronson 10,  Nigel Gj Richards 11,  William C Hahn 6 7,  Amy J Wagers 1 5
Affiliations

Affiliations

  • 1 Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States.
  • 2 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, United States.
  • 3 Pediatric Hematology/Oncology, Charité, University Hospital Berlin, Berlin, Germany.
  • 4 Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
  • 5 Joslin Diabetes Center, Harvard Medical School, Boston, United States.
  • 6 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.
  • 7 Broad Institute of Harvard and MIT, Cambridge, United States.
  • 8 Summer Honors Undergraduate Program, Harvard Medical School, Boston, United States.
  • 9 University of Maryland, Baltimore County, Baltimore, United States.
  • 10 Department of Biomedical Sciences, Tufts University Veterinary School, North Grafton, United States.
  • 11 Department of Chemistry and Chemical Biology, Indiana University - Purdue University Indianapolis, Indianapolis, United States.
PMID: 26499495 DOI: 10.7554/eLife.09436
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 disruption of 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.

Keywords

asparaginase; asparagine synthetase; cell biology; developmental biology; functional genomics; human; mouse; rhabdomyosarcoma; sarcoma; stem cells.

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