Communications Biology (Aug 2024)

Cytidine deaminase-dependent mitochondrial biogenesis as a potential vulnerability in pancreatic cancer cells

  • Audrey Frances,
  • Audrey Lumeau,
  • Nicolas Bery,
  • Marion Gayral,
  • Lucille Stuani,
  • Marie Sorbara,
  • Estelle Saland,
  • Delphine Pagan,
  • Naïma Hanoun,
  • Jérôme Torrisani,
  • Anthony Lemarié,
  • Jean-Charles Portais,
  • Louis Buscail,
  • Nelson Dusetti,
  • Jean-Emmanuel Sarry,
  • Pierre Cordelier

DOI
https://doi.org/10.1038/s42003-024-06760-y
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 11

Abstract

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Abstract 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.