Dissecting the Role of Cross-talk Between Glioblastoma Subpopulations in Tumor Cell Spreading

Glioblastoma multiforme (GBM) is a highly infiltrative brain cancer, rendering the tumor difficult to operate. GBM cells frequently harbor Epidermal Growth Factor Receptor amplification (EGFRwt) or activating mutation (EGFRvIII), generating at least two different cellular subpopulations within the tumor. We examine the relationship between the diffusive architectures of GBM tumors and paracrine interactions between those subpopulations. We establish a methodology that quantifies the infiltration abilities of cancer cells through computation of cell-cell separation distance distributions in 3D cultures.

We have found that aggressive EGFRvIII cells modulate the migration and infiltrative properties of EGFRwt cells via HGF and IL6, secreted by EGFRvIII cells. This leads to enhanced activity of Src protein in EGFRwt cells, induced velocity and ability to spread of EGFRwt cells. Src inhibitor, Dasatinib, which is used at low non-toxic concentrations, reduces the infiltrative properties of EGFRvIII/ EGFRwt neurospheres. Furthermore the drug actively generates compact multicellular microstructures in which EGFRvIII/ EGFRwt cells are getting packed and do not spread. Prevention of cellular infiltration or induction of those microstructures may enhance the probability of GBM tumors to be detected in the brains and to be removed successfully by surgery.