Journal
CELL
Volume 174, Issue 6, Pages 1559-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.07.019
Keywords
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Categories
Funding
- Weizmann Institute
- Basque Biobank for Research (BIOEF)
- European Research Program [CIG618113, ERC614204]
- Israel Science Foundation [1343/13, 1952/13, 41/11, 696/17]
- Minerva [711730]
- Adelis Foundation
- Henry S. and Anne S. Reich Research Fund
- Dukler Fund for Cancer Research
- Paul Sparr Foundation
- Saul and Theresa Esman Foundation
- Joseph Piko Baruch
- estate of Fannie Sherr
- I-CORE Center of Excellence in Gene Regulation in Complex Human Disease
- IPST
- NIST
- NIH [R33 CA225291]
- Basque Department of Industry, Tourism, and Trade (Etortek) and Education [IKERTALDE I.T.1106-16]
- BBVA Foundation
- MINECO [SAF2016-79381-R]
- MSCA-ITN-ETN [721532]
- European Research Council Starting Grant [336343]
- European Research Council Proof-of-Concept Program [754627]
- FEDER fund
- NSF award [1564785]
- Intramural Research Program of the NIH
- National Institute on Aging
- ERC-2016-PoC [754282]
- NATIONAL CANCER INSTITUTE [R33CA225291, ZIABC011802] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [ZIAAG000750] Funding Source: NIH RePORTER
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The urea cycle (UC) is the main pathway by which mammals dispose of waste nitrogen. We find that specific alterations in the expression of most UC enzymes occur in many tumors, leading to a general metabolic hallmark termed UC dysregulation'' (UCD). UCD elicits nitrogen diversion toward carba-moyl- phosphate synthetase2, aspartate transcarbamylase, and dihydrooratase (CAD) activation and enhances pyrimidine synthesis, resulting in detectable changes in nitrogen metabolites in both patient tumors and their bio-fluids. The accompanying excess of pyrimidine versus purine nucleotides results in a genomic signature consisting of transversion mutations at the DNA, RNA, and protein levels. This mutational bias is associated with increased numbers of hydrophobic tumor antigens and a better response to immune checkpoint inhibitors independent of mutational load. Taken together, our findings demonstrate that UCD is a common feature of tumors that profoundly affects carcinogenesis, mutagenesis, and immunotherapy response.
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