Cytidine deaminase regulates mitochondrial biogenesis in pancreatic cancer cells

ABSTRACT Despite tremendous efforts from the scientific community, pancreatic ductal adenocarcinoma (PDAC) is still a deadly disease and will soon become the second cause of death by cancer worldwide 1 . When surgery is not possible, therapeutic options are few and ineffective 2 . Patients are most often treated with Folfirinox or gemcitabine chemotherapy, that extends survival in weeks to months. Cytidine deaminase (CDA) catalyzes the irreversible hydrolytic deamination of cytidine and deoxycytidine to uridine and deoxyuridine to fuel RNA and DNA synthesis 3 . CDA also deaminates and neutralizes deoxycytidine-based therapies, and as such, has been identified as a major contributor of tumor chemoresistance, especially to gemcitabine in PDAC 3 . We previously identified that CDA is elevated in PDAC tumors at diagnosis and that CDA exerts an unexpected role on DNA replication that can be exploited for therapeutic intervention 4 . Very recently, CDA was associated with cellular metabolism 5 . Here, we show that CDA promotes mitochondrial biogenesis and oxidative phosphorylation independently of its deaminase activity. This uncloaks novel therapeutic vulnerabilities in primary cancer cells that overexpress this protein. This study shines a new light on the tumoral potential of CDA in PDAC.