Description du projet
Disséquer les mécanismes moléculaires sous-jacents à la résistance à la radiothérapie
La radiothérapie constitue un traitement courant du cancer, mais malgré sa réussite, elle est entravée par l’émergence de la résistance locale et de métastases distantes. Le principal objectif du projet TETHER, financé par l’UE, consiste à découvrir les mécanismes moléculaires sous-jacents à la résistance à la radiothérapie. Les chercheurs réaliseront une édition des gènes dans des modèles murins uniques et dans des organoïdes afin de cartographier le réseau fonctionnel de gènes qui jouent un rôle considérable dans la résistance à la radiothérapie. La délimitation des mécanismes utilisés par les cellules cancéreuses pour échapper à la radiothérapie fournira des informations importantes sur la conception d’approches personnalisées pour améliorer la réponse du traitement chez les patients atteints d’un cancer.
Objectif
"More than 50% of the cancer patients undergo irradiation as part of their cancer treatment. Although radiotherapy (RT) significantly contributes to cancer cure, local therapy resistance and the subsequent emergence of distant metastasis remain major obstacles for its success. The molecular mechanisms underlying tumor cell-intrinsic RT resistance are ill-defined. It is therefore crucial to better define these mechanisms and identify new vulnerabilities of RT-resistant tumors in order to decrease the current annual cancer mortality of >1.3 million persons in EU member states alone.
In the TETHER project, I will address the problem of RT resistance by synergizing the power of genetic essentiality analyses with unique mouse models and organoids that we have established. We recently found that members of the shieldin and CST complexes are essential for tumor cells to survive irradiation, while causing PARP inhibitor resistance when lost in BRCA1-deficient tumors. Based on this unexpected finding, I have started a new line of research to dissect the RT ""essentialome"". As I show with the discovery and functional characterization of ERCC6l2 as a novel DNA repair factor in this network, the technology we have in place is perfectly suited to tackle this question. In addition, we will apply distinct CRISPR/Cas9-based tests to map the functional interactome of genes that are essential for RT resistance.
To follow the plasticity and RT escape of tumor cells in vivo, we have also developed innovative model systems. Similar to the situation in cancer patients, we observe that residual cancer cells in our mouse models escape the deadly effects of RT by local resistance or metastasis formation. Thus, these models provide a unique opportunity to explore and target RT escape mechanisms. I am convinced that the combination of these state-of-the-art approaches will yield highly useful information for designing individualized approaches to improve RT response in cancer patients.
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Champ scientifique
Programme(s)
Thème(s)
Régime de financement
ERC-ADG - Advanced GrantInstitution d’accueil
3012 Bern
Suisse