Uncovering the effects of DNA replication stress on cell fate determination in cancer and stem cells

Several studies have indicated that most cancer cells are associated with stress caused by the perturbation of DNA replication inducing replication stress (RS). RS and in general genome instability are major causes of genetic and epigenetic heterogeneity in human tumors. However, despite this heterogeneity, tumor mass and metastasis display stereotypical behaviors that allow them to invade surrounding tissues and escape immune surveillance. These features are remarkably similar to the ones displayed by trophoblast cells supporting placenta development. Using mouse embryonic stem cells (ESCs) we have recently found that RS-mediated activation of ATR and CHK1 promotes the expression of thousands of genes many of which involved in trophoblast differentiation, suggesting that RS can impact on cell fate determination in stem cells. The activation of several of these genes is coordinated by DUX, the master regulator of the two-cell stage in mouse ESCs, which we showed to be required for multinucleated trophoblast giant cells differentiation in response to RS. DUX and its human ortholog DUX4 are suppressed in normal adult cells. However, they are specifically reactivated in tumors where they promote the emergence of trophoblast-like features. Here we will study the molecular mechanisms linking RS to trophoblast activation in ESCs, identify pathways shared between placenta and cancer cells and uncover the mechanisms that suppress placenta activating mechanisms in adult somatic cells. Our studies will set the stage for targeting these pathways in order to develop new and effective therapeutic strategies to eradicate tumors.