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

• DOI: 10.1093/neuonc/noad210
• Publication Date: 2023-11-08T06:34:22Z
• Authors: Sarah J Derby; Louise Dutton; Karen E Strathdee; Katrina Stevenson; Anna Koessinger; Mark Jackson; Yuling Tian; Wenxi Yu; Kathy Mclay; Josette Misquitta; Sama Alsharif; Cassie J Clarke; Lesley Gilmour; Peter Thomason; Ewan McGhee; Connor L McGarrit...; Aurelie Vanderlinden; Spencer J Collis; Ola Rominyi; Leandro Lemgruber; Gergely Solecki; Michael Olson; Frank Winkler; Leo M Carlin; Dieter Henrik Hei...; Gareth J Inman; Anthony J Chalmers; Jim C Norman; Ross Carruthers; Joanna L Birch
• Keywords: Internalization; Intravital microscopy

Abstract 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 counter glioblastoma invasion. Here, we report inhibition of ataxia telangiectasia Rad 3 related kinase (ATR) reduces invasion cells through dysregulation cytoskeletal networks subsequent integrin trafficking. Methods Glioblastoma motility were assessed in vitro vivo response ATR (ATRi) overexpression using time-lapse microscopy, two orthotopic models, intravital imaging. Disruption cytoskeleton endocytic processing investigated via high-throughput, super-resolution Results High expression was associated with significantly poorer survival clinical datasets while histological, protein expression, spatial transcriptomics tumor specimens revealed higher at margins. Pharmacological different compounds RNAi targeting opposed the glioblastoma, whereas drove migration. Subsequent investigation reduced macropinocytotic internalization integrins growth-cone-like structures, resulting microtube retraction defect. The biological relevance translational potential these findings confirmed models Conclusions We demonstrate novel role for determining propose pharmacological could far-reaching benefits beyond radiosensitization.