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.


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*


  • 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