Carruthers, R. D. et al. (2018) Replication stress drives constitutive activation of the DNA damage response and radioresistance in glioblastoma stem-like cells. Cancer Research, 78(17), pp. 5060-5071. (doi: 10.1158/0008-5472.CAN-18-0569) (PMID:29976574) (PMCID:PMC6128404)
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Abstract
Glioblastoma (GBM) is a lethal primary brain tumor characterized by treatment resistance and inevitable tumor recurrence, both of which are driven by a subpopulation of GBM cancer stem-like cells (GSC) with tumorigenic and self-renewal properties. Despite having broad implications for understanding GSC phenotype, the determinants of upregulated DNA damage response (DDR) and subsequent radiation resistance in GSC are unknown and represent a significant barrier to developing effective GBM treatments. In this study, we show that constitutive DDR activation and radiation resistance are driven by high levels of DNA replication stress (RS). CD133+ GSC exhibited reduced DNA replication velocity and a higher frequency of stalled replication forks than CD133- non-GSC in vitro; immunofluorescence studies confirmed these observations in a panel of orthotopic xenografts and human GBM specimens. Exposure of non-GSC to low-level exogenous RS generated radiation resistance in vitro, confirming RS as a novel determinant of radiation resistance in tumor cells. GSC exhibited DNA double strand breaks (DSB) which co-localized with 'replication factories' and RNA: DNA hybrids. GSC also demonstrated increased expression of long neural genes (>1Mbp) containing common fragile sites, supporting the hypothesis that replication/transcription collisions are the likely cause of RS in GSC. Targeting RS by combined inhibition of ATR and PARP (CAiPi) provided GSC-specific cytotoxicity and complete abrogation of GSC radiation resistance in vitro. These data identify RS as a cancer stem cell-specific target with significant clinical potential.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Carruthers, Dr Ross and Gilmour, Dr Lesley and Ahmed, Dr Shafiq and Stevenson, Mrs Katrina and Strathdee, Mrs Karen and Kalna, Dr Gabriela and Neilson, Dr Matthew and Chalmers, Professor Anthony |
| Authors: | Carruthers, R. D., Ahmed, S. U., Ramachandran, S., Strathdee, K., Kurian, K. M., Hedley, A., Gomez-Roman, N., Kalna, G., Neilson, M. P., Gilmour, L., Stevenson, K. H., Hammond, E. M., and Chalmers, A. J. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Cancer Research |
| Publisher: | American Association for Cancer Research |
| ISSN: | 0008-5472 |
| ISSN (Online): | 1538-7445 |
| Published Online: | 05 July 2018 |
| Copyright Holders: | Copyright © 2018 American Association for Cancer Research |
| First Published: | First published in Cancer Research 78(17): 5060-5071 |
| Publisher Policy: | Reproduced in accordance with the publisher copyright policy |
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