Cytidine deaminase-dependent mitochondrial biogenesis as a potential vulnerability in pancreatic cancer cells
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.
Authors
- Nelson Dusetti (ORCID: https://orcid.org/0000-0002-6161-8483)
- Naı̈ma Hanoun (ORCID: https://orcid.org/0009-0006-8511-4788)
- Nicolas Béry (ORCID: https://orcid.org/0000-0002-2643-3897)
- Lucille Stuani (ORCID: https://orcid.org/0000-0001-6116-981X)
- Jérôme Torrisani (ORCID: https://orcid.org/0000-0001-6880-9357)
- Audrey Francès
- Marion Gayral (ORCID: https://orcid.org/0009-0000-3175-1139)
- Marie Sorbara
- Audrey Lumeau (ORCID: https://orcid.org/0000-0003-0431-3736)
- Jean‐Emmanuel Sarry (ORCID: https://orcid.org/0000-0002-6704-2032)
- Delphine Pagan (ORCID: https://orcid.org/0000-0002-8298-3682)
- Anthony Lemarié (ORCID: https://orcid.org/0000-0002-6523-4962)
- Étienne Buscail (ORCID: https://orcid.org/0000-0003-2040-3045)
- Jean‐Charles Portais (ORCID: https://orcid.org/0000-0002-3480-0933)
- Pierre Cordelier (ORCID: https://orcid.org/0000-0003-2096-7967)
- Estelle Saland (ORCID: https://orcid.org/0000-0001-8521-3061)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Université Toulouse III - Paul Sabatier (FR)
- Inserm (FR)
- Université Fédérale de Toulouse Midi-Pyrénées (FR)
- Institut National des Sciences Appliquées de Toulouse (FR)
- Centre de Recherches en Cancérologie de Toulouse (FR)
- La Ligue Contre le Cancer (FR)
- Hôpital Rangueil (FR)
- Centre de Recherche en Cancérologie de Marseille (FR)
Publication Details
- Journal
- Communications Biology
- Published
- 2024-08-30
- DOI
- https://doi.org/10.1038/s42003-024-06760-y
- Citations
- 7
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 1.98
Funders
- Institut National de la Santé et de la Recherche Médicale
- Ligue Contre le Cancer
- Fondation de France
- Région Occitanie Pyrénées-Méditerranée
- Fondation Toulouse Cancer Santé
- Inserm Transfert