Investigating the contribution of ageing mechanisms to glioblastoma treatment resistance. (360G-Wellcome-319160_Z_24_Z)

Ageing is the greatest contributing factor to developing glioblastoma (GBM). Older patients have the least favourable outcomes. After surgery, disease recurs from where tumorous cells have invaded into the healthy brain. There is a need to understand the cellular interactions beyond the typically resected tumour at the glioma-brain-interface, and how biological mechanisms associated with brain ageing influences tumour treatment response and recurrence for these patients. One such mechanism is quiescence, which is influenced by inflammation present in ageing brains. Quiescent cells evade cytotoxic and anti-mitotic treatments. My hypothesis is that brain ageing in astrocytes directs quiescence in glioblastoma cells that remain after surgery, causing greater treatment resistance. This will be tested by four objectives: (i) Study the multi-cellular transcriptome as tumours extend into the healthy brain in patient samples. This will utilise spatial, single-cell RNA sequencing in surgical samples across the invasive margin older patients’ tumours; (ii) Compare this to a brain ageing model in patient-derived GSC models, including those generated from matched surgical samples in (i); (iii) Determine how brain ageing influences treatment response in this model; (iv) Define ex-vivo and in-vitro transcriptomic patterns associated with increasing age and treatment response, and validate correlating pathways using targeted therapeutics screening.