이주상 (National Institute of Health, University of Maryland)

한빛사논문

조회2,178

National Institute of Health, University of Maryland

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Cell, Published:August 09, 2018 | DOI:https://doi.org/10.1016/j.cell.2018.07.019 Urea Cycle Dysregulation Generates Clinically Relevant Genomic and Biochemical Signatures

Joo Sang Lee,^1,2,22 Lital Adler,^3,22 Hiren Karathia,² Narin Carmel,³ Shiran Rabinovich,³ Noam Auslander,^1,2 Rom Keshet,³Noa Stettner,^3,4 Alon Silberman,³ Lilach Agemy,⁵ Daniel Helbling,⁶ Raya Eilam,⁴ Qin Sun,⁷ Alexander Brandis,⁸ Sergey Malitsky,⁸ Maxim Itkin,⁸ Hila Weiss,³ Sivan Pinto,³ Shelly Kalaora,⁹ Ronen Levy,⁹ Eilon Barnea,¹⁰ Arie Admon,¹⁰ David Dimmock,¹¹ Noam Stern-Ginossar,¹² Avigdor Scherz,⁴ Sandesh C.S. Nagamani,^7,13 Miguel Unda,^14,15 David M. Wilson III,¹⁶ Ronit Elhasid,¹⁷ Arkaitz Carracedo,^15,18,19,20 Yardena Samuels,⁹ Sridhar Hannenhalli,² Eytan Ruppin,^1,2,21,23,* and Ayelet Erez^3,23,24,*¹Cancer Data Science Lab, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

²Center for Bioinformatics and Computational Biology, University of Maryland Institute for Advanced Computer Studies, Department of Computer Science, University of Maryland, College Park, MD 20742, USA

³Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel

⁴Department of Veterinary Resources, Weizmann Institute of Science, 7610001 Rehovot, Israel

⁵Department of Plant and Environmental Science, Weizmann Institute of Science, 7610001 Rehovot, Israel

⁶Envision Genomics, Huntsville, AL 35806, USA

⁷Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA

⁸Life Sciences Core Facilities, Weizmann Institute of Science, 7610001 Rehovot, Israel

⁹Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel

¹⁰Faculty of Biology, Technion - Israel Institute of Technology, 3200003 Haifa, Israel

¹¹Rady Children’s Institute for Genomic Medicine, San Diego, CA 92123, USA

¹²Department of Molecular Genetics, Weizmann Institute of Science, 7610001 Rehovot, Israel

¹³Texas Children’s Hospital, Houston, TX 77030, USA

¹⁴Department of Urology, Basurto University Hospital, 48013 Bilbao, Spain

¹⁵CIBERONC, Madrid, Spain

¹⁶Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program, NIH, 251 Bayview Blvd., Baltimore, MD 21224, USA

¹⁷Sackler Faculty of Medicine, Department of Pediatric Hemato Oncology, Sourasky Medical Center, Tel Aviv University, 6997801 Tel Aviv, Israel

¹⁸CIC bioGUNE, Bizkaia Technology Park, 801 Building, 48160 Derio, Spain

¹⁹Ikerbasque, Basque Foundation for Science, Bilbao, Spain

²⁰Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), Bilbao, Spain

²¹Schools of Medicine and Computer Science, Tel Aviv University, 6997801 Tel Aviv, Israel

²²These authors contributed equally

²³These authors contributed equally

²⁴Lead Contact

^*Correspondence: Eytan Ruppin, Ayelet Erez

Abstract

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 carbamoyl-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.

논문정보

형식Research article
게재일2018년 08월 (BRIC 등록일 2018-08-21)
연구진국외 연구진
분야 의약학 > 유전 및 유전체의학

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