Crosstalk between two Glioblastoma subpopulations modulates tumoral migration and survival, in response to radiotherapy

Glioblastoma (GBM) is the most malignant and highly infiltrative brain tumor. GBM growth and invasion are very complex processes, evolving several intracellular signaling pathways, such as EGFR (Epidermal Growth Factor Receptor), leading to poor prognosis and antitherapy resistance. GBM tumors harbor several subpopulations, including EGFRwt subpopulation, consisting of cells overexpressing wild type of EGFR, and EGFRvIII subpopulation expressing a constitutively active EGFR.

Radiotherapy (RT), a standard treatment of GBM, was recently found to be implicated in the GBM invasion within the brain. Here, we examine the role of crosstalk between EGFRwt and EGFRVIII subpopulations in GBM spreading under radiotherapy.

EGFRwt and EGFRvIII U87 cells, plus patient-derived GBM cells harboring the same subpopulations, were seeded in monocultures or cocultures in 2D/3D cultures or injected stereotactically into murine brains. Where after, cells or brains were irradiated to analyze the spreading abilities of the cells.

Our preliminary results have shown, that RT enhances significantly the migratory properties of EGFRwt subpopulation when cocultured with GBM EGFRvIII cells as examined in-vitro and in-vivo. This communication involves SRC-mediated pathway. We found that RT induces another ongoing process in EGFRvIII/EGFRwt population, which includes STAT3/ STAT1 pathways. Computational analysis suggested that the Src- and Stat3/1-related processes are distinct. Thus experiments are underway to examine the relationships between the SRC and STAT3 pathways, also to validate their in-vivo role in GBM responses to radiation.

In conclusion, our work suggests that the cell-cell communication between two GBM subpopulations contributes significantly to Glioblastoma infiltration and survival in response to radiotherapy.