Inhibition of ATR opposes glioblastoma invasion through disruption of cytoskeletal networks and integrin internalisation via macropinocytosis

Derby, S. et al. (2024) Inhibition of ATR opposes glioblastoma invasion through disruption of cytoskeletal networks and integrin internalisation via macropinocytosis. Neuro-Oncology, (doi: 10.1093/neuonc/noad210) (PMID:37936324) (Early Online Publication)

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Background: Glioblastomas have highly infiltrative growth patterns that contribute to recurrence and poor survival. Despite infiltration being a critical therapeutic target, no clinically useful therapies exist that counter glioblastoma invasion. Here, we report that inhibition of ataxia telangiectasia and Rad 3 related kinase (ATR) reduces invasion of glioblastoma cells through dysregulation of cytoskeletal networks and subsequent integrin trafficking. Methods: Glioblastoma motility and invasion were assessed in vitro and in vivo in response to ATR inhibition (ATRi) and ATR overexpression using time-lapse microscopy, two orthotopic glioblastoma models, and intravital imaging. Disruption to cytoskeleton networks and endocytic processing were investigated via high-throughput, super-resolution and intravital imaging. Results: High ATR expression was associated with significantly poorer survival in clinical datasets while histological, protein expression, and spatial transcriptomics using glioblastoma tumor specimens revealed higher ATR expression at infiltrative margins. Pharmacological inhibition with two different compounds and RNAi targeting of ATR opposed the invasion of glioblastoma, whereas overexpression of ATR drove migration. Subsequent investigation revealed that cytoskeletal dysregulation reduced macropinocytotic internalization of integrins at growth-cone-like structures, resulting in a tumor microtube retraction defect. The biological relevance and translational potential of these findings were confirmed using two orthotopic in vivo models of glioblastoma and intravital imaging. Conclusions: We demonstrate a novel role for ATR in determining invasion in glioblastoma cells and propose that pharmacological targeting of ATR could have far-reaching clinical benefits beyond radiosensitization.

Item Type:Articles
Status:Early Online Publication
Glasgow Author(s) Enlighten ID:Derby, Dr Sarah and Misquitta, Ms Josette and Carruthers, Dr Ross and Inman, Professor Gareth and Birch, Dr Joanna and Norman, Professor James and Jackson, Dr Mark and Lemgruber Soares, Dr Leandro and Stevenson, Mrs Katrina and Koessinger, Dr Anna and Strathdee, Mrs Karen and Alsharif, Miss Sama and Clarke, Dr Cassie and Dutton, Ms Louise and Chalmers, Professor Anthony and Gilmour, Dr Lesley and Mclay, Miss Kathy and Olson, Professor Michael and Carlin, Dr Leo
Authors: Derby, S., Dutton, L., Strathdee, K.E., Stevenson, K., Koessinger, A., Jackson, M., Yuling, T., Yu, W., Mclay, K., Misquitta, J., Alsharif, S., Clarke, C.J., Gilmour, L., Thomason, P., McGhee, E., McGarrity-Cottrell, C.L., Vanderlinden, A., Collis, S.J., Rominyi, O., Lemgruber, L., Solecki, G., Olson, M., Winkler, F., Carlin, L.M., Heiland, D.H., Inman, G., Chalmers, A.J., Norman, J.C., Carruthers, R., and Birch, J.L.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Neuro-Oncology
Publisher:Oxford University Press
ISSN (Online):1523-5866
Published Online:04 November 2023
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in Neuro-Oncology 2024
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
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