Project description
Dissecting the molecular mechanisms underlying radiotherapy resistance
Radiotherapy is a common cancer treatment, but despite its success, it is hampered by the emergence of local resistance and distant metastases. The key objective of the EU-funded TETHER project is to unveil the molecular mechanisms underlying radiotherapy resistance. Researchers will perform gene editing in unique mouse models and organoids to map the functional network of genes that play a significant role in radiotherapy resistance. Delineation of the mechanisms used by cancer cells to escape radiotherapy will provide important insight into the design of personalised approaches to improve treatment response in cancer patients.
Objective
"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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Fields of science
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Funding Scheme
ERC-ADG - Advanced GrantHost institution
3012 Bern
Switzerland