Replication stress drives constitutive activation of the DNA damage response and radioresistance in glioblastoma stem-like cells

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)

[img]
Preview
Text
165442.pdf - Accepted Version

3MB

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:Strathdee, Mrs Karen and Ahmed, Dr Shafiq and Kalna, Dr Gabriela and Neilson, Dr Matthew and Chalmers, Professor Anthony and Carruthers, Dr Ross and Gilmour, Dr Lesley and Stevenson, Mrs Katrina
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 > Institute 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

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
737161Investigating elevated DNA replication stress in glioblastoma stem cells and neural stem cells and exploiting its therapeutic potential.Ross CarruthersCancer Research UK (CRUK)C52808/A23920RI CANCER SCIENCES