Effect of focused ultrasound-induced mechanical ablation on stemness and dormancy properties of residual/peri-focally localized glioblastoma cells

Background Focused ultrasound (FUS) is a new technology that enables the spatially and temporally precise delivery of ultrasound energy to various targets. In addition to its known applications in treating tumors, cavitation-based mechanical focused ultrasound (mFUS) is gaining importance. Due to the novelty of this technique, little is known about the effects of mFUS on peri-focally localized or surviving tumor cells. Glioblastomas (GBMs) are highly malignant intracranial tumors with a pronounced intra- and intertumoral heterogeneity, which, e.g., leads to their evasion of appropriate treatment regimens. Methods The impact of mFUS was investigated in patient-derived GBM organoids (GBOs), glioma stem-like cells (GSCs), and differentiated GBM cells in an in vitro 3D hydrogel culture model. Particular attention was paid to investigating the stemness and dormancy properties of residual/peri-focally localized GBM cells, as these may be important for tumor progression. Results In GBOs and different primary cells, increased expression of dormancy- and stemness-associated markers was found in a complex region- and marker-dependent manner mediated via PI3-kinase/Akt/GSK3β signaling, suggesting an effect of mFUS beyond the focal area. mFUS resulted in an increased ability of residual/peri-focal, formerly differentiated patient-derived GBM cells to form stem cell-typical spheres associated with increased expression of various dormancy and stemness markers. Residual/peri-focal patient-derived cells were characterized by a higher resistance to temozolomide, resulting in fewer dead cells compared to temozolomide treatment alone. Conclusion The ablation of defined regions by mFUS appears to regulate the stemness and dormancy properties of the residual/peri-focally localized GBM cells in a region-specific manner.