ECOLE DOCTORALE "Médicament, Toxicologie, Chimie, Imageries"
- UNIVERSITE PARIS DESCARTES
Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2016-
2017
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Nom, prénom du directeur de l'unité de recherche :Ludger Johannes
Numéro de l'unité de recherche (et établissement de rattachement) : UMR 3666
Nom, prénom du responsable de l'équipe d'accueil (EAD) : Raphaël Rodriguez
Nom, prénom du directeur de thèse : Raphaël Rodriguez
Titre du sujet de thèse proposé : Targeting iron metabolism in cancer stem cells
Contenu scientifique du programme de la thèse
We aim to develop drugs that selectively target cancer stem cells (CSCs), the main cause of drug
resistance and cancer relapse, for which there is currently no clinically approved treatment. We have
previously shown that the natural product salinomycin (Figure 1) and its synthetic derivative ironmycin
do not operate as ionophores but target instead the lysosomal compartment and interact with iron(II),
thereby preventing release of the metal into the cytosol. This in turns leads to cellular iron depletion
and the production of lethal reactive oxygen species in this organelle. Our study revealed that iron
homeostasis is upregulated in cancer stem cells and represents a druggable network.
In the first part of this project, we will develop new drugs based on our prototype drug ironomycin
that already exhibits a 10-fold increased potency compared to salinomycin with improved selectivity
CSCs vs normal cancer cells. In the second part of this project, we aim to elucidate the role of iron in
the maintenance of CSCs. We have recently found (unpublished results) that endothelial-to-
mesenchymal transition (EMT) in cancer models requires iron. Thus, we hypothesized that the
epigenetic reprogramming that promote EMT is mediated by iron-dependent enzymes. In particular,
TET and Jumonji enzymes have previously been shown to regulate the epigenetic landscape through
iron-mediated oxidative demethylation processes. This project will combine state-of-the-art
chemistry and cell biology.
Figure 1: Molecular structure of salinomycin (upper panel) and ironomycin (lower panel)
Salinomycin kills cancer stem cells by sequestering iron in lysosomes. Trang Thi Mai, Ahmed
Hamaï, Antje Hienzsch, Tatiana Cañeque, Sebastian Müller, Julien Wicinski, Olivier Cabaud,
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