Glioblastoma cells have increased capacity to repair radiation-induced DNA damage after migration to the olfactory bulb
Abstract Background The invasive nature of GBM combined with the diversity of brain microenvironments creates the potential for a topographic heterogeneity in GBM radioresponse. Investigating the mechanisms responsible for a microenvironment-induced differential GBM response to radiation may provide...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-12-01
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| Series: | Cancer Cell International |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12935-022-02819-0 |
| _version_ | 1811179144718843904 |
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| author | Charlotte Degorre Ian C. Sutton Stacey L. Lehman Uma T. Shankavaram Kevin Camphausen Philip J. Tofilon |
| author_facet | Charlotte Degorre Ian C. Sutton Stacey L. Lehman Uma T. Shankavaram Kevin Camphausen Philip J. Tofilon |
| author_sort | Charlotte Degorre |
| collection | DOAJ |
| description | Abstract Background The invasive nature of GBM combined with the diversity of brain microenvironments creates the potential for a topographic heterogeneity in GBM radioresponse. Investigating the mechanisms responsible for a microenvironment-induced differential GBM response to radiation may provide insights into the molecules and processes mediating GBM radioresistance. Methods Using a model system in which human GBM stem-like cells implanted into the right striatum of nude mice migrate throughout the right hemisphere (RH) to the olfactory bulb (OB), the radiation-induced DNA damage response was evaluated in each location according to γH2AX and 53BP1 foci and cell cycle phase distribution as determined by flow cytometry and immunohistochemistry. RNAseq was used to compare transcriptomes of tumor cells growing in the OB and the RH. Protein expression and neuron–tumor interaction were defined by immunohistochemistry and confocal microscopy. Results After irradiation, there was a more rapid dispersal of γH2AX and 53BP1 foci in the OB versus in the RH, indicative of increased double strand break repair capacity in the OB and consistent with the OB providing a radioprotective niche. With respect to the cell cycle, by 6 h after irradiation there was a significant loss of mitotic tumor cells in both locations suggesting a similar activation of the G2/M checkpoint. However, by 24 h post-irradiation there was an accumulation of G2 phase cells in the OB, which continued out to at least 96 h. Transcriptome analysis showed that tumor cells in the OB had higher expression levels of DNA repair genes involved in non-homologous end joining and genes related to the spindle assembly checkpoint. Tumor cells in the OB were also found to have an increased frequency of soma–soma contact with neurons. Conclusion GBM cells that have migrated to the OB have an increased capacity to repair radiation-induced double strand breaks and altered cell cycle regulation. These results correspond to an upregulation of genes involved in DNA damage repair and cell cycle control. Because the murine OB provides a source of radioresistant tumor cells not evident in other experimental systems, it may serve as a model for investigating the mechanisms mediating GBM radioresistance. |
| first_indexed | 2024-04-11T06:30:55Z |
| format | Article |
| id | doaj.art-acc01da916514c0a8e8f39bc81e249be |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-04-11T06:30:55Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj.art-acc01da916514c0a8e8f39bc81e249be2022-12-22T04:40:06ZengBMCCancer Cell International1475-28672022-12-0122111310.1186/s12935-022-02819-0Glioblastoma cells have increased capacity to repair radiation-induced DNA damage after migration to the olfactory bulbCharlotte Degorre0Ian C. Sutton1Stacey L. Lehman2Uma T. Shankavaram3Kevin Camphausen4Philip J. Tofilon5Radiation Oncology Branch, National Cancer InstituteRadiation Oncology Branch, National Cancer InstituteRadiation Oncology Branch, National Cancer InstituteRadiation Oncology Branch, National Cancer InstituteRadiation Oncology Branch, National Cancer InstituteRadiation Oncology Branch, National Cancer InstituteAbstract Background The invasive nature of GBM combined with the diversity of brain microenvironments creates the potential for a topographic heterogeneity in GBM radioresponse. Investigating the mechanisms responsible for a microenvironment-induced differential GBM response to radiation may provide insights into the molecules and processes mediating GBM radioresistance. Methods Using a model system in which human GBM stem-like cells implanted into the right striatum of nude mice migrate throughout the right hemisphere (RH) to the olfactory bulb (OB), the radiation-induced DNA damage response was evaluated in each location according to γH2AX and 53BP1 foci and cell cycle phase distribution as determined by flow cytometry and immunohistochemistry. RNAseq was used to compare transcriptomes of tumor cells growing in the OB and the RH. Protein expression and neuron–tumor interaction were defined by immunohistochemistry and confocal microscopy. Results After irradiation, there was a more rapid dispersal of γH2AX and 53BP1 foci in the OB versus in the RH, indicative of increased double strand break repair capacity in the OB and consistent with the OB providing a radioprotective niche. With respect to the cell cycle, by 6 h after irradiation there was a significant loss of mitotic tumor cells in both locations suggesting a similar activation of the G2/M checkpoint. However, by 24 h post-irradiation there was an accumulation of G2 phase cells in the OB, which continued out to at least 96 h. Transcriptome analysis showed that tumor cells in the OB had higher expression levels of DNA repair genes involved in non-homologous end joining and genes related to the spindle assembly checkpoint. Tumor cells in the OB were also found to have an increased frequency of soma–soma contact with neurons. Conclusion GBM cells that have migrated to the OB have an increased capacity to repair radiation-induced double strand breaks and altered cell cycle regulation. These results correspond to an upregulation of genes involved in DNA damage repair and cell cycle control. Because the murine OB provides a source of radioresistant tumor cells not evident in other experimental systems, it may serve as a model for investigating the mechanisms mediating GBM radioresistance.https://doi.org/10.1186/s12935-022-02819-0RadioresistanceGlioblastomaMicroenvironment |
| spellingShingle | Charlotte Degorre Ian C. Sutton Stacey L. Lehman Uma T. Shankavaram Kevin Camphausen Philip J. Tofilon Glioblastoma cells have increased capacity to repair radiation-induced DNA damage after migration to the olfactory bulb Cancer Cell International Radioresistance Glioblastoma Microenvironment |
| title | Glioblastoma cells have increased capacity to repair radiation-induced DNA damage after migration to the olfactory bulb |
| title_full | Glioblastoma cells have increased capacity to repair radiation-induced DNA damage after migration to the olfactory bulb |
| title_fullStr | Glioblastoma cells have increased capacity to repair radiation-induced DNA damage after migration to the olfactory bulb |
| title_full_unstemmed | Glioblastoma cells have increased capacity to repair radiation-induced DNA damage after migration to the olfactory bulb |
| title_short | Glioblastoma cells have increased capacity to repair radiation-induced DNA damage after migration to the olfactory bulb |
| title_sort | glioblastoma cells have increased capacity to repair radiation induced dna damage after migration to the olfactory bulb |
| topic | Radioresistance Glioblastoma Microenvironment |
| url | https://doi.org/10.1186/s12935-022-02819-0 |
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