Final Report Summary - STEMRENEWAL (Identification of a new mechanism of stem cell self-renewal; direct implications on self-repair and tumor initiating cells in the brain)
In the adult brain, stem cell cells reside in the subventricular zone in a defined microenvironment (or stem cell niche) consisting of ependymal cells, transit amplifying progenitors and neuroblasts and in the subgranular zone of the hippocampus. Neurogenesis continues in the adult brain throughout life and may play important roles of learning and memory, as well as in diseases such as anxiety and depression. We have reported a new mechanism regulating stem cell numbers in the adult brain. This mechanism is highly unexpected and unconventional as it involves GABAA receptor signaling in neural stem cells resulting in modifications of histone H2AX which controls proliferation of the stem cells in the S-phase of the cell cycle. Our data supports a view where this mechanism underlies a homeostatic suppression of neural stem cell proliferation that may contribute to changes in stem cell numbers and neurogenesis associated with neurological diseases as well as the limited self-repair capacity of the damaged brain. We have also identified a similar mechanism in brain cancer stem cells (i.e. glioblastoma cells) and this signaling significantly affects survival and disease outcome. In a large effort spanning five years, glioblastoma cells were also found vulnerable to macropinocytic vacuolization and death. We hypothesized that gain- and loss-of-function mutations lead to acquired functions also in cellular pathways not necessarily involved in cell transformation. Such properties could be exploited for development of conceptually new therapeutic strategies. Based on this assumption, we performed a small molecule screen and identified the selective vulnerability of human glioblastoma stem-like cells to catastrophic vacuolization and necrotic-like death. These results exemplifies to our knowledge for the first time that the marked changes in biology underlying cell transformation also can lead to gained functions resulting in a vulnerability of the cancer cell. We have showed that this mechanism readily can be targeted by a small molecule with excellent in vivo pharmacokinetics and brain exposure, and that when administered by orally (by ingestion), it significantly attenuates infiltration, tumor growth and markedly extends survival in glioblastoma animal models. These results point to the possible exploitation of this cellular process in the design of anticancer therapies.