Background: Developing therapy resistance and exhibiting high invasiveness are significant challenges in treating aggressive cancers, such as glioblastoma, where intercellular communication plays a crucial role in cellular organization, survival, and resistance to treatment. Tunneling nanotubes (TNTs), nanometer-sized membranous channels that connect distant cells, have emerged as an efficient form of intercellular communication that may enable cancer cells to evade therapeutic interventions. Methods: In this study, we investigated the responses of TNT networks to low linear energy transfer (low-LET) X-ray irradiation in two established glioblastoma cell lines, U87 MG and LN229. Initially, we assessed radiosensitivity using colony formation assays to measure cell survival. Then, we used confocal live-cell microscopy to monitor TNT network dynamics over a 24-hour period following irradiation and performed co-staining experiments to identify cargoes transported through TNTs. Results: We observed a significant increase in TNT-mediated cellular connectivity 6 to 10 hours after 1.8 Gy X-ray irradiation in both cell lines. In contrast, cells treated with a higher radiation dose (3.9 Gy) exhibited reduced TNT connectivity; however, it remained slightly elevated compared to sham-irradiated controls. The co-staining experiments revealed the presence of calcium and mitochondria within TNTs. These cargoes are known to facilitate cancer cell migration and survival, potentially contributing to treatment resistance. Conclusions: Taken together, these results strongly suggest that TNT-mediated intercellular communication may be a critical mechanism that supports glioblastoma resistance to radiotherapy.
Matejka et al. (Wed,) studied this question.
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