Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma.
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.
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.
Simone
S
Hettmer
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.|Broad Institute of Harvard and MIT, Cambridge, United States.
Anna C
AC
Schinzel
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.
Daria
D
Tchessalova
Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
Michaela
M
Schneider
Summer Honors Undergraduate Program, Harvard Medical School, Boston, United States.|University of Maryland, Baltimore County, Baltimore, United States.
Christina L
CL
Parker
Department of Biomedical Sciences, Tufts University Veterinary School, North Grafton, United States.
Roderick T
RT
Bronson
Department of Chemistry and Chemical Biology, Indiana University - Purdue University Indianapolis, Indianapolis, United States.
Nigel Gj
NG
Richards
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.|Broad Institute of Harvard and MIT, Cambridge, United States.
William C
WC
Hahn
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.
Amy J
AJ
Wagers
D000818:Animals; D001216:Asparagine / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D020868:Gene Silencing; D005820:Genetic Testing; D006801:Humans; D053858:Metabolic Networks and Pathways; D051379:Mice; D012509:Sarcoma / Q000503:physiopathology*
D001216:Asparagine
asparaginase; asparagine synthetase; cell biology; developmental biology; functional genomics; human; mouse; rhabdomyosarcoma; sarcoma; stem cells