Tumor cell network integration in glioma represents a stemness feature

Area of Science:

• Neuro-oncology
• Cancer Biology
• Cellular Heterogeneity

Background:

• Malignant gliomas, including glioblastomas, display significant cellular heterogeneity.
• A critical subpopulation of glioma cells achieves high resistance through integration into tumor microtube (TM)-connected multicellular networks.

Purpose of the Study:

• To establish a novel functional approach for detecting, isolating, and characterizing glioma cell subpopulations based on their in vivo network integration.
• To investigate the molecular and functional characteristics of network-integrated glioma cells.

Main Methods:

• Combination of dye staining, intravital two-photon microscopy, Fluorescence-Activated Cell Sorting (FACS), molecular profiling, and gene reporter studies.
• In vivo tracking of tumor cell nestin expression.

Main Results:

• TM-connected glioblastoma cells exhibit activated neurodevelopmental and glioma progression gene expression pathways.
• Network-integrated cells show increased stemness (high nestin expression) and enhanced potential for brain tumor reinitiation.
• Nestin-high, network-integrated glioblastoma cells demonstrate higher radioresistance and adapt to radiotherapy by increasing TM formation.

Conclusions:

• A fraction of network-integrated glioma cells is enriched with multiple stem-like features, contributing to their pronounced resilience.
• Understanding these network-integrated, stem-like glioma cells is crucial for developing more effective glioblastoma therapies.