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Rôle de la cytidine désaminase dans le contrôle du métabolisme énergétique tumoral pancréatique

Abstract : Pancreatic cancer is one of the cancers with the worst prognosis, with a 5-year survival rate of less than 10%. Combined with a rising incidence in developed countries and a silent progression that delays diagnosis, this cancer is likely to become one of the deadliest in the world in the folowing years. There is therefore an urgent need to better understand the molecular mechanisms that govern pancreatic carcinogenesis in order to improve the diagnosis and management of patients with this illness. It was in this context that my team became interested in cytidine deaminase (CDA). Indeed, CDA has been studied in pancreatic cancer for decades for its role in chemo-resistance, but its functional importance in pancreatic carcinogenesis had never been explored before. First of all, my team highlighted that CDA is overexpressed in pancreatic cancers compared to healthy tissue, and that it is a factor of worse prognosis. In addition, its depletion in vitro and in vivo in experimental models of pancreatic cancer induces a drastic drop in cell proliferation, prevents tumor growth and leads to cell death by apoptosis. Thus, these preliminary results highlight the functional importance of CDA in pancreatic carcinogenesis. These results gave rise to my thesis work, which aim was to study the role of CDA in the control of pancreatic tumor energy metabolism. Proteomic and transcriptomic studies revealed an altered energy metabolic signature in CDA-depleted pancreatic cancer cells against control cells. My thesis results first showed that the invalidation of CDA induces an energetic reprogramming of cells, triggered in the short term by a defect in the mitochondrial pool. Indeed, CDA-depleted cells show a decrease in their mitochondrial mass, accompanied by a decrease in mitochondrial DNA (mtDNA). In the long term, these cells accumulate mitochondrial dysfunctions, such as impaired respiration and mitochondrial ATP production and overproduction of reactive oxygen species (ROS). They also up-regulate their key glycolytic enzymes and tend to increase their glucose and glutamine uptake.[...]
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Audrey Frances. Rôle de la cytidine désaminase dans le contrôle du métabolisme énergétique tumoral pancréatique. Cancer. Université Paul Sabatier - Toulouse III, 2019. Français. ⟨NNT : 2019TOU30212⟩. ⟨tel-02934249⟩

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