Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma
Simone Hettmer,
Anna C Schinzel,
Daria Tchessalova,
Michaela Schneider,
Christina L Parker,
Roderick T Bronson,
Nigel GJ Richards,
William C Hahn,
Amy J Wagers
Affiliations
Simone Hettmer
Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, United States; Pediatric Hematology/Oncology, Charité, University Hospital Berlin, Berlin, Germany; Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany; Joslin Diabetes Center, Harvard Medical School, Boston, United States
Anna C Schinzel
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; Broad Institute of Harvard and MIT, Cambridge, United States
Daria Tchessalova
Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States; Joslin Diabetes Center, Harvard Medical School, Boston, United States
Michaela Schneider
Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany
Christina L Parker
Summer Honors Undergraduate Program, Harvard Medical School, Boston, United States; University of Maryland, Baltimore County, Baltimore, United States
Roderick T Bronson
Department of Biomedical Sciences, Tufts University Veterinary School, North Grafton, United States
Nigel GJ Richards
Department of Chemistry and Chemical Biology, Indiana University - Purdue University Indianapolis, Indianapolis, United States
William C Hahn
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; Broad Institute of Harvard and MIT, Cambridge, United States
Amy J Wagers
Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States; Joslin Diabetes Center, Harvard Medical School, Boston, United States
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.
