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

Abstract

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, eg 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.