Urea cycle dysregulation, emerging pyrimidines mutation bias and enhanced response to immunotherapy in cancer

The urea cycle (UC) is the main metabolic pathway by which mammals dispose waste nitrogen. Here we show that the expression of most UC enzymes is altered in many tumors, leading to a general metabolic hallmark that we term UC dysregulation (UCD). UCD elicits nitrogen diversion towards 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 bio-fluids. The accompanying excess of pyrimidine vs purine nucleotides results in a novel genomic signature consisting of transversion mutations at the DNA, RNA and protein levels. This mutational bias is associated with more hydrophobic tumor antigens and with a better response to immune checkpoint inhibitors, independent of mutational load. Taken together, our findings demonstrate that UCD is a common feature of tumors, which profoundly impacts carcinogenesis, mutagenesis and immunotherapy response.

[Joint work with the Erez lab at the Weizmann Institute, Israel]