Mechanosensing and routes of glioblastoma dissemination

Abstract

Gliomas are the most common malignant primary brain tumours, with high-grade gliomas (HGG), such as glioblastoma multiforme (GBM), exhibiting strong resistance to standard treatments like surgical resection and chemoradiation. Despite decades of research, patient outcomes remain poor, underscoring the need to better understand therapeutic failure.

The tumour microenvironment (TME) plays a crucial role in driving tumour heterogeneity, invasion, and therapy resistance. While biochemical factors of the TME have been widely studied, recent focus has turned to its mechanical properties and how these influence GBM migration and adaptation. The failure of promising preclinical therapies in clinical settings is increasingly attributed to gaps in understanding the TME’s biomechanics, mechanotransduction pathways, and interactions with surrounding cells.

This thesis investigates the impact of cell-cell interactions on HGG migration using a 3D spheroid model with patient-derived GBM cells cultured on biomechanically relevant substrates. Findings revealed distinct and shared migration patterns across cell lines, shaped by cell-cell and cell-substrate dynamics, potentially mediated by focal adhesions (FA), and largely independent of GBM subtype. In vivo studies using a mouse xenograft model with the same cell lines further highlighted the roles of EGFR and FAK signalling in guiding GBM invasion. A systematic review of the brain’s viscoelastic properties under health, disease, and treatment conditions revealed a lack of longitudinal data on mechanical changes post-therapy—an essential gap for advancing precise treatments.

Collectively, this work emphasises the importance of TME mechanics in GBM progression and therapy resistance, offering insights for the development of more effective interventions for this devastating disease.