Urea Cycle Dysregulation Generates Clinically Relevant Genomic and Biochemical Signatures

Joo Sang Lee; Lital Adler; Hiren Karathia; Narin Carmel; Shiran Rabinovich; Noam Auslander; Rom Keshet; Noa Stettner; Alon Silberman; Lilach Agemy; Daniel Helbling; Raya Eilam; Qin Sun; Alexander Brandis; Sergey Malitsky; Maxim Itkin; Hila Weiss; Sivan Pinto; Shelly Kalaora; Ronen Levy; Eilon Barnea; Arie Admon; David Dimmock; Noam Stern-Ginossar; Avigdor Scherz; Sandesh C S Nagamani; Miguel Unda; David M Wilson 3rd; Ronit Elhasid; Arkaitz Carracedo; Yardena Samuels; Sridhar Hannenhalli; Eytan Ruppin; Ayelet Erez

doi:10.1016/j.cell.2018.07.019

Urea Cycle Dysregulation Generates Clinically Relevant Genomic and Biochemical Signatures

Cell. 2018 Sep 6;174(6):1559-1570.e22. doi: 10.1016/j.cell.2018.07.019. Epub 2018 Aug 9.

Authors

Joo Sang Lee¹, Lital Adler², Hiren Karathia³, Narin Carmel², Shiran Rabinovich², Noam Auslander¹, Rom Keshet², Noa Stettner⁴, Alon Silberman², Lilach Agemy⁵, Daniel Helbling⁶, Raya Eilam⁷, Qin Sun⁸, Alexander Brandis⁹, Sergey Malitsky⁹, Maxim Itkin⁹, Hila Weiss², Sivan Pinto², Shelly Kalaora¹⁰, Ronen Levy¹⁰, Eilon Barnea¹¹, Arie Admon¹¹, David Dimmock¹², Noam Stern-Ginossar¹³, Avigdor Scherz⁷, Sandesh C S Nagamani¹⁴, Miguel Unda¹⁵, David M Wilson 3rd¹⁶, Ronit Elhasid¹⁷, Arkaitz Carracedo¹⁸, Yardena Samuels¹⁰, Sridhar Hannenhalli³, Eytan Ruppin¹⁹, Ayelet Erez²⁰

Affiliations

¹ Cancer Data Science Lab, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Center 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.
² Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel.
³ Center 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.
⁴ Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel; Department of Veterinary Resources, Weizmann Institute of Science, 7610001 Rehovot, Israel.
⁵ Department of Plant and Environmental Science, Weizmann Institute of Science, 7610001 Rehovot, Israel.
⁶ Envision Genomics, Huntsville, AL 35806, USA.
⁷ Department of Veterinary Resources, Weizmann Institute of Science, 7610001 Rehovot, Israel.
⁸ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
⁹ Life Sciences Core Facilities, Weizmann Institute of Science, 7610001 Rehovot, Israel.
¹⁰ Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel.
¹¹ Faculty of Biology, Technion - Israel Institute of Technology, 3200003 Haifa, Israel.
¹² Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
¹³ Department of Molecular Genetics, Weizmann Institute of Science, 7610001 Rehovot, Israel.
¹⁴ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
¹⁵ Department of Urology, Basurto University Hospital, 48013 Bilbao, Spain; CIBERONC, Madrid, Spain.
¹⁶ Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program, NIH, 251 Bayview Blvd., Baltimore, MD 21224, USA.
¹⁷ Sackler Faculty of Medicine, Department of Pediatric Hemato Oncology, Sourasky Medical Center, Tel Aviv University, 6997801 Tel Aviv, Israel.
¹⁸ CIBERONC, Madrid, Spain; CIC bioGUNE, Bizkaia Technology Park, 801 Building, 48160 Derio, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain; Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), Bilbao, Spain.
¹⁹ Cancer Data Science Lab, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Center 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; Schools of Medicine and Computer Science, Tel Aviv University, 6997801 Tel Aviv, Israel. Electronic address: ayelet.erez@weizmann.ac.il.
²⁰ Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel. Electronic address: eyruppin@gmail.com.

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.

Keywords: CAD; cancer metabolism; immunotherapy; mutagenesis; pyrimidines; urea cycle.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amino Acid Transport Systems, Basic / metabolism
Animals
Aspartate Carbamoyltransferase / genetics
Aspartate Carbamoyltransferase / metabolism
Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / genetics
Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / metabolism
Cell Line, Tumor
Dihydroorotase / genetics
Dihydroorotase / metabolism
Female
Genomics*
Humans
Metabolomics*
Mice
Mice, Inbred C57BL
Mice, SCID
Mitochondrial Membrane Transport Proteins
Neoplasms / metabolism
Neoplasms / pathology*
Ornithine Carbamoyltransferase / antagonists & inhibitors
Ornithine Carbamoyltransferase / genetics
Ornithine Carbamoyltransferase / metabolism
Phosphorylation / drug effects
Pyrimidines / biosynthesis
Pyrimidines / chemistry
RNA Interference
RNA, Small Interfering / metabolism
Sirolimus / pharmacology
TOR Serine-Threonine Kinases / antagonists & inhibitors
TOR Serine-Threonine Kinases / metabolism
Urea / metabolism*

Substances

Amino Acid Transport Systems, Basic
CAD trifunctional enzyme
Mitochondrial Membrane Transport Proteins
Pyrimidines
RNA, Small Interfering
SLC25A15 protein, human
Urea
Aspartate Carbamoyltransferase
Ornithine Carbamoyltransferase
MTOR protein, human
TOR Serine-Threonine Kinases
Dihydroorotase
Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)
pyrimidine
Sirolimus

Abstract

Publication types

MeSH terms

Substances

Grants and funding