Ricerc@Sapienza

Glioblastomas (GBMs) are brain tumors of glial origin characterized by a heavy hypoxic microenvironment, which correlates with tumor aggressiveness. The failure of current therapies is mainly to be ascribed to the high capacity of GBM cells to migrate and invade the surrounding brain parenchyma and to resist to conventional treatments. GBM cells abundantly express large-conductance, calcium-activated potassium (BK) channels that are thought to be involved in cell migration, proliferation and death. The mechanisms controlling the hypoxia-induced aggressive phenotype are however still unclear. Low oxygen levels experienced by cancer cells within a solid tumor favor the maintenance of an undifferentiated state of the so called Cancer Stem Cells, which drive GBM growth, invasion and reccurrence. The mechanisms underlying the regulation of differentiation of Glioma Stem Cells (GSCs) need to be investigated, as well as the influence of hypoxia in promoting the ¿dedifferentiation¿ of the more differentiated cancer cells. Our preliminary data indicate that BK channels are involved in the hypoxia-induced chemoresistance and clonogenic ability of human U87-MG GBM cells when exposed to Cisplatin. Moreover, in our previous study we have already demonstrated an overexpression of BK channels in GSCs and their important contribution in the migration and differentiation of this subpopulation.
In the light of our observations, we hypothesize an important role for BK channels in many aspects of the hypoxia-induced aggressive behavior of GBM cells, namely chemoresistance, clonogenic ability and differentiation capacity.
In the present project we propose the following two aims:
- to clarify the molecular mechanisms underlying the contribution of BK channels in the resistance and clonogenic expansion of GBM cells induced by hypoxia;
- to evaluate the involvement of BK channels in the regulation of the differentiation of GBM cells in presence of low oxygen concentrations.