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A systematic approach to find new cancer molecules: an enhancer trap screen to identify

Final Activity Report Summary - ES-TRAP (A systematic approach to find new cancer molecules: an enhancer trap screen to identify)

In recent years, the public interest as well as scientific research into the nature of stem cells has exploded. The term 'stem cell' has been used for cells with many diverse aspects including embryonic stem cells (ES cells), adult stem cells but also cancer stem cells. The defining aspect of all of these stem cells is a potent ability to self-renew in a seemingly limitless fashion. This term self-renewal describes the ability of a stem cell to go through numerous cycles of cell division while always maintaining the identical state: remaining entirely undifferentiated. In addition to this ability for self-renewal, there is a classical definition of a stem cell that asks these cells to possess an additional property: a potency or the capacity to differentiate into specialised cell types.

Since this specific potency is not always shared by cancer stem cells, this definition may strictly be applied only for adult and embryonic stem cells. Only these former types of stem cells are always considered either totipotent or pluripotent. This potency to be able to give rise to any mature cell type of an adult organism is naturally highly desirable to understand. Multi- or uni- potent types of transient progenitors lack the full spectrum of such differentiation programs, but are still sometimes referred to as stem cells. Moreover, it is easily understandable that cancer stem cells may be impaired in their ability to respond to cues to differentiate to all lineages of an adult body. Lastly, the overall fascination with stem cells can be clearly credited to the fascinating pluripotent abilities of ES cells.

The ES-TRAP project wanted to understand more about the ability of ES cells for pluri-potency. Since a therapeutic usage of these ES cells is hindered by our lack to clearly separate various stages of differentiation we wanted to find novel markers for the pluripotent stage but also the first, early phase of transition to differentiation. Still, ES cells may in the near future be used for new therapies, either by themselves or through cellular replacement strategies. Here, the considerable challenge will be to rule out that none of the cells used in clinical trials remain undifferentiated, since ES cells in this state cause cancers. ES-TRAP used ES cells as an in vitro model of early mammalian developmental stages. We used a genetic screen and specific differentiation protocols to identify novel regulators of self-renewal in ES cells. ES-TRAP team members characterized these regulators of pluri-potency including novel chromatin regulators, as well as the Sprouty family. Using a number of cell biological and biochemical analysis ES-TRAP revealed that inhibitors of the RAS-signalling pathway are expressed in early embryos, are required for maintenance of ES cell pluri-potency and essential to suppress the default extra-embryonic development. Altogether, our results show that the tight regulation of specific signalling pathways is vital to maintain the pluripotent state of ES cells. Ultimately, we can prove that there is not necessarily an inherent link between differentiation and proliferation in ES cells.

ES-TRAP delivered as planned to enable a young research team, centred round a young team leader, with trans-national mobility and high priority for gender and the potential for excellence. The career of all members of the team was developed successfully. ES-TRAP also fulfilled its objectives to generate results, which in the long run may assist to reach clinical results. Lastly, ES-TRAP generated results for a possible patent development publication and a deeper understanding about the ability of ES cells for pluri-potency.