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| Home > Publications database > Radioresistance and transcriptional reprograming of invasive glioblastoma cells. |
| Journal Article | DKFZ-2021-02233 |
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2022
Elsevier Science
Amsterdam [u.a.]
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Please use a persistent id in citations: doi:10.1016/j.ijrobp.2021.09.017
Abstract: Infiltrative growth pattern is a hallmark of glioblastoma (GBM). Radiotherapy aims to eradicate microscopic residual GBM cells post-surgical removal of the visible tumor bulk. However, in field recurrences remain the major pattern of therapy failure. We hypothesized that the radiosensitivity of peripheral invasive tumor cells (peri) may differ from predominantly investigated tumor bulk.Invasive GBM populations were generated via debulking of the visible tumor core and serial orthotopic transplantation of peri cells and sustained pro-invasive phenotype of peri cell was confirmed in-vitro by scratch assay and time lapse imaging. In parallel, invasive GBM cells were selected by transwell assay and from peri cells of patient derived 3D spheroid cultures. Transcriptome analysis deciphered a GBM invasion associated gene signature and functional involvement of key pathways was validated by pharmacological inhibition.Compared to the bulk cells, invasive GBM populations acquired a radioresistant phenotype characterized by increased cell survival, reduced cell apoptosis and enhanced DNA double strand break (DSB) repair proficiency. Transcriptome analysis revealed a reprograming of invasive cells towards augmented activation of EGFR and NF-κB related pathways while metabolic processes were downregulated. An invasive GBM score (iGS) derived from this transcriptional fingerprint correlated well with patient outcome. Inhibition of EGFR and NF-κB signaling re-sensitized invasive cells to irradiation. Invasive cells were eradicated with similar efficacy by particle therapy with carbon ions.Our data indicate that invasive tumor cells constitute a phenotypically distinct and highly radioresistant GBM subpopulation with prognostic impact that may be vulnerable to targeted therapy and carbon-ions.
Keyword(s): EGFR, NF-κB ; GBM ; carbon-ions ; invasion ; radioresistance
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