Targeting the energy production process in pancreatic cancer cells, which relies on an enzyme called cytidine deaminase, could make these cells more vulnerable

Cytidine deaminase (CDA) converts cytidine and deoxycytidine into uridine and deoxyuridine as part of the pyrimidine salvage pathway. Elevated levels of CDA are found in pancreatic tumors and associated with chemoresistance. Recent evidence suggests that CDA has additional functions in cancer cell biology. In this work, we uncover a novel role of CDA in pancreatic cancer cell metabolism. CDA silencing impairs mitochondrial metabolite production, respiration, and ATP production in pancreatic cancer cells, leading to a so-called Pasteur effect metabolic shift towards glycolysis. Conversely, we find that CDA expression promotes mitochondrial biogenesis and oxidative phosphorylation, independently of CDA deaminase activity. Furthermore, we observe that patient primary cells overexpressing CDA are more sensitive to mitochondria-targeting drugs. Collectively, this work shows that CDA plays a non-canonical role in pancreatic cancer biology by promoting mitochondrial function, which could be translated into novel therapeutic vulnerabilities.

This translational oncology research program highlights, for the first time, the crucial role of CDA in regulating mitochondrial biogenesis, particularly in the context of a major public health issue, pancreatic adenocarcinoma.

This work could help for a more precise selection of pancreatic cancer patients who might benefit more from mitochondria targeting agents, based on the expression level of CDA in the tumor, following a precision medicine approach. In addition to exploring other functions of CDA, we are currently developing new targeting approaches for this enzyme, aiming to enhance the sensitivity of pancreatic tumors to therapies targeting DNA replication.

Mitochondrial network in CDA-depleted cells (electronic microscopy)

Collaborations and partnerships

Collaborations :

• CRCT : équipes Metaml (Sarry) et Radopt (Moyal)
• Service de gastroentérologie et de pancréatologie, CHU Rangueil, Université de Toulouse, Toulouse, France
• Restore
• Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Université Aix-Marseille, Marseille, France

Founding :

• Fondation Toulouse Cancer Santé,
• Ligue Nationale Contre le Cancer,
• Fondation de France,
• Région Occitanie,
• Inserm