Tumor initiation and oncogenic stress David Domínguez-Solà
- Normal control of DNA replication by c-Myc. We know now that in a physiologic context, c-Myc directs the initiation of DNA synthesis. This non-transcriptional function of c-Myc is essential for its role in cell growth and proliferation, and our recent description has opened a new research field. Part of our scientific efforts will be dedicated to understand with greater detail how c-Myc exerts this replicative function, and to integrate our findings with previous knowledge on c-Myc oncoprotein biological activities.
- Biologic origin of c-Myc-derived oncogenic stress, and its relevance for tumor initiation. In tumors, deregulation of c-Myc’s normal activity on DNA replication leads to the appearance of DNA damage events and the activation of DNA damage-repair and checkpoint pathways. However, we still do not know the molecular mechanisms that underlie this effect, nor do we know whether these events are required for c-Myc-dependent tumor initiation. We are interested in answering these questions, which we intend to do by combining molecular biology approaches and animal models generated to this purpose.
- Genetic interactions between oncogenic stress and the mechanisms of genome surveillance and DNA repair. One of the important predictions of our working model is that c-Myc deregulation would interact genetically with possible disfunctions of those pathways involved in DNA replication stability and DNA damage-repair. Predictably, these interactions could have synergistic effects on tumor initiation. The existence of these interactions would be, in part, a proof of principle for the relevance of oncogenic stress in Myc-dependent tumorigenesis, but at the same time, would prompt the identification of novel diagnostic and prognostic markers, and more importantly, help define novel therapeutic targets.