Targeting Potassium Channels to Reprogram Glioblastoma Microenvironment: in Vitro and in Vivo Studies

Specific Aim 1:

Specific Aim 3:

To investigate whether M, or Mf-derived micro-vesicles, delivered to the brain of mouse bearing glioma could affect glioma growth and mice survival. This will allow to better define the role of M in controlling glioma growth as a function of its activation state and of KCa3.1 and Kv1.3 channel expression and activity. OBJECTIVE: from this aim the investigators expect to verify whether brain delivery of differently polarized M (or M-derived vesicles), or M/Mf, could represent a meaningful approach to counteract glioma growth and to lengthen mice survival.

Investigate the relationship between CD11b+ and NK cells upon KCa3.1 and Kv1.3 inhibition or NK cell depletion. OBJECTIVE: data obtained will help to understand whether the activation state of M/Mf affects NK cell accumulation in the tumor site and their cytotoxic activity, whether NK cells modulate M/Mf activation, with effects on tumor growth, and the eventual role played by K+ channels. Our preliminary data showing that TRAM-34 treatment increased the mRNA level of IL-15 in the brain of glioma-bearing mice (FIG3) would suggest an IL-15-mediated increased accumulation of NK cells in the tumor region, similarly to previous evidence (19).

To investigate the roles of KCa3.1 and Kv1.3 channels in the interaction between glioma and the surrounding parenchyma. OBJECTIVE: to identify possible mechanisms of altered communication in the brain of mice treated with K+ channel inhibitors by studying K+ currents, excitatory and inhibitory synaptic transmission and astrocytes activation state, under normal and hypoxic conditions (corresponding to different position in the tumor mass). Altered expression and function of ion channels in glioma cells isolated from mice treated with functionally different M and M-derived vesicles will also be investigated.