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Les mécanismes moléculaires de la méthionine dépendance des cellules souches cancéreuses

Abstract : Some cancer cells are methionine dependent however little is known about the mechanisms of this dependency. Tumor initiating cells are a rare population of cancer cells, implicated in disease recurrence, that phenocopy cancer stem cells and form 3D spheroids or ‘tumor spheres (TS)» under non adherent conditions. We show that, unlike U251 adherent monolayer cells, TS derived from U251 glioblastoma cells need exogenous methionine to grow. This methionine dependency is characterized by a bell shape curve in which high methionine concentrations (>0.01mM) slow down TS growth. During methionine restriction, 5- methyltetrahydrofolate restores TS formation. When TS are deprived from methionine for 24h, then supplemented with folic acid, they exhibit lower levels of folate isoforms than adherent cells maintained in the same conditions, suggesting that folate cycle is repressed in TS relative to adherent cells. Functional annotation of the RNA-seq data shows clear changes in several molecular functions and reveals in TS a reduced cell cycle, an increased stemness and a diminished folate metabolism affecting particularly DHFR, SHMT and MTFHD. Methylome analysis shows methylation changes in cell cycle, stemness and folate cycle, despite global DNA methylation patterns remaining stable. However, unlike the important promoter methylation observed for cell cycle and stemness genes (+25%), only 10 folate cycle genes out of 139 genes involved in one-carbon metabolism are significantly altered. In conclusion, reduced folate cycle is part of the metabolic reprogramming triggering dedifferenciation into cancer stem cells and this repression is only partly explained by the alteration of promoter methylation
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Submitted on : Wednesday, July 11, 2018 - 10:41:13 AM
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  • HAL Id : tel-01835090, version 1

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Racha Zgheib. Les mécanismes moléculaires de la méthionine dépendance des cellules souches cancéreuses. Médecine humaine et pathologie. Université de Lorraine, 2017. Français. ⟨NNT : 2017LORR0342⟩. ⟨tel-01835090⟩

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