We made important contributions to the field of genome stability and tumor biology by shedding light on new mechanisms and pathways controlling genome stability and HRD tumor survival.
One of the objectives of our ERC StG was to understand the mechanisms of action of polymerase theta and the underlying reason for the synthetic lethality with HR. We have solved this question, by showing the Polθ repairs DSB during mitosis and that this function is essential for the survival of HR deficient cells. More generally, in our ERC StG project, we aimed at discovering additional DNA repair related vulnerabilities of HR-deficient tumors. We discovered new targetable synthetic lethality with HR-defect. One of our studies unveils nuclear NAD+-mediated DAN repair as a novel vulnerability of BRCA1/2-mutated cancer cells and its potential as druggable signaling pathway to tackle PARPi resistance. In another work, we discovered that BRCA1/2-mutated tumors show frequent events of nuclear envelop rupture and that inhibiting the repair of these ruptures kills BRCA1/2-mutated cells. This constitutes a novel and targetable vulnerability, which we termed NE vulnerability.
Our reseach and results were disseminated by several members of our groups (PI, postdocs and PhD) through various means to the scientific community and to non-specialist audiences. First, we published new biological insights in high quality, international peer-reviewed open access journals to allow for a maximum dissemination (Nature, Nature Cancer, Molecular Cell). Second, we have presented our work at national and international conferences dedicated to basic biophysical, DNA replication and DNA repair studies such as EMBO conferences, Keystone symposia and biophysical societies. Third, we have presented seminars to several research institute in Europe. These events are important as they represent an opportunity to reach out to all components of our scientific community (technician, undergrads, PhD, administrative), and not only those attending international conferences. Finally, we have presented our research and discoveries to non-specialist audiences (communication at elementary school, radio, TV), and at national and local science events. Innovation also took a part important of our action. We have also demonstrated our potential to bridge basic to translational science by developing the first-in-class Polθ inhibitor (now in clinical trials), filing 5 patents, obtaining funds for innovation (i.e. ERC PoC) and by creating a startup developing new anti-cancer therapeutics.
