Tmic-35. astrocyte-dependent enhancement of glioblastoma growth as a candidate therapeutic target

Glioblastoma multiforme (GBM) is a disease with an urgent need for deeper understanding and new therapeutic approaches. As in other solid tumors, the tumor microenvironment (TME) is likely to control growth and sensitivity to treatment. Key components of the TME of GBM include the vasculature, microglia and astrocytes. Whereas GBM vasculature and microglia have been extensively studied, less is known about the potential involvement of astrocytes in GBM biology. In this study, astrocytes were investigated with regard to their effect on glioblastoma growth through in vitro approaches and in an in vivo model. Our studies, using different established GBM cell lines, and patient-derived primary GBM cultures, show that co-cultured astrocytes increase GBM cell number by supporting GBM cell proliferation. Furthermore, orthotopic co-injection of astrocytes and GBM cells in mice leads to reduced survival as compared to GBM cell mono-injection. Gene-expression analyses of mono- or co-cultured astrocytes have identified a GBM-cell-induced astrocyte gene signature. Analyses of two publically available GBM gene expression data set demonstrated that the signature of “GBM-educated” astrocytes was associated with significantly shorter survival. These analyses also indicated differences between molecular subgroups of GBM regarding the signature, such that the mesenchymal subset displayed a higher signature score as compared to the other molecular GBM subtypes. A high-throughput screening of approximately 1200 compounds of the “Prestwick-library” has been performed to identify compounds which specifically block the astrocyte-dependent proliferation of U343MG GBM cells. Following the initial screen, 12 compounds have been validated as specifically acting on GBM growth in co-culture. Two of them have been selected for further studies. In summary, this ongoing study suggests that astrocytes contribute to glioblastoma growth and implies this crosstalk as a candidate target for novel therapies. Clinical relevance of the model system is suggested by the prognostic significance of the signature of GBM-educated astrocytes.