Targeting radiation-tolerant persister cells as a strategy for inhibiting radioresistance and recurrence in glioblastoma. Issue 7 (14th December 2021)

• Record Type: Journal Article
• Authors: Gu, Jintao; Mu, Nan; Jia, Bo; Guo, Qingdong; Pan, Luxiang; Zhu, Maorong; Zhang, Wangqian; Zhang, Kuo; Li, Weina; Li, Meng; Wei, Lichun; Xue, Xiaochang; Zhang, Yingqi; Zhang, Wei
• Is Part Of: Neuro-oncology. Volume 24:Issue 7(2022)
• Page Start: 1056
• Page End: 1070
• Publication Date: 2021-12-14
• Subjects: DNA damage repair -- glioblastoma -- glioma stem cell -- radioresistance; Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noab288
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Background: Compelling evidence suggests that glioblastoma (GBM) recurrence results from the expansion of a subset of tumor cells with robust intrinsic or therapy-induced radioresistance. However, the mechanisms underlying GBM radioresistance and recurrence remain elusive. To overcome obstacles in radioresistance research, we present a novel preclinical model ideally suited for radiobiological studies. Methods: With this model, we performed a screen and identified a radiation-tolerant persister (RTP) subpopulation. RNA sequencing was performed on RTP and parental cells to obtain mRNA and miRNA expression profiles. The regulatory mechanisms among NF-κB, YY1, miR-103a, XRCC3, and FGF2 were investigated by transcription factor activation profiling array analysis, chromatin immunoprecipitation, western blot analysis, luciferase reporter assays, and the MirTrap system. Transferrin-functionalized nanoparticles (Tf-NPs) were employed to improve blood–brain barrier permeability and RTP targeting. Results: RTP cells drive radioresistance by preferentially activating DNA damage repair and promoting stemness. Mechanistic investigations showed that continual radiation activates the NF-κB signaling cascade and promotes nuclear translocation of p65, leading to enhanced expression of YY1, the transcription factor that directly suppresses miR-103a transcription. Restoring miR-103a expression under these conditions suppressed the FGF2–XRCC3 axis and decreased the radioresistance capability. Moreover, Tf-NPs improved radiosensitivity and provided a significant survival benefit. Conclusions: We suggest that the NF-κB–YY1–miR-103a regulatory axis is indispensable for the function of RTP cells in driving radioresistance and recurrence. Thus, our results identified a novel strategy for improving survival in patients with recurrent/refractory GBM. Graphical Abstract: