Ruppin Co-Authors Study on the Behavior of Cancer Cells

Eytan Ruppin, a professor of computer science and director of the Center for Bioinformatics and Computational Biology (CBCB), has co-authored a study on the behavior of cancer cells, which was recently published in the journal Nature.

The study, “Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis," explores how cancer cells hijack and remodel existing metabolic pathways for their benefit. Argininosuccinate synthase (ASS1) is a urea cycle enzyme that is essential in the conversion of nitrogen from ammonia and aspartate to urea. A decrease in nitrogen flux through ASS1 in the liver causes the urea cycle disorder, citrullinaemia. In contrast to the well-studied consequences of loss of ASS1 activity on ureagenesis, the purpose of its somatic silencing in multiple cancers is largely unknown.

In this study, the researchers show that decreased activity of ASS1 in cancers supports proliferation by facilitating pyrimidine synthesis via CAD (carbamoyl-phosphate synthase 2, aspartate transcarbamylase, and dihydroorotase complex) activation. Decreasing CAD activity by blocking citrin, the mTOR signalling, or pyrimidine synthesis decreases proliferation and thus may serve as a therapeutic strategy in multiple cancers where ASS1 is down-regulated. Their results demonstrate that ASS1 down-regulation is a novel mechanism supporting cancerous proliferation, and that ASS1 down-regulation provides a metabolic link between the urea cycle enzymes and pyrimidine synthesis.