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Tumor cell network integration in glioma represents a stemness feature

2020; Oxford University Press; Volume: 23; Issue: 5 Linguagem: Inglês

10.1093/neuonc/noaa275

1523-5866

Ruifan Xie, Tobias Keßler, Julia Grosch, Ling Hai, Varun Venkataramani, Lulu Huang, Dirk C. Hoffmann, Gergely Solecki, Miriam Ratliff, Matthias Schlesner, Wolfgang Wick, Frank Winkler,

Cell Image Analysis Techniques

Malignant gliomas including glioblastomas are characterized by a striking cellular heterogeneity, which includes a subpopulation of glioma cells that becomes highly resistant by integration into tumor microtube (TM)-connected multicellular networks. A novel functional approach to detect, isolate, and characterize glioma cell subpopulations with respect to in vivo network integration is established, combining a dye staining method with intravital two-photon microscopy, Fluorescence-Activated Cell Sorting (FACS), molecular profiling, and gene reporter studies. Glioblastoma cells that are part of the TM-connected tumor network show activated neurodevelopmental and glioma progression gene expression pathways. Importantly, many of them revealed profiles indicative of increased cellular stemness, including high expression of nestin. TM-connected glioblastoma cells also had a higher potential for reinitiation of brain tumor growth. Long-term tracking of tumor cell nestin expression in vivo revealed a stronger TM network integration and higher radioresistance of the nestin-high subpopulation. Glioblastoma cells that were both nestin-high and network-integrated were particularly able to adapt to radiotherapy with increased TM formation. Multiple stem-like features are strongly enriched in a fraction of network-integrated glioma cells, explaining their particular resilience.