CBIO-33INVESTIGATING GLIOMA CELL PHENOTYPES WITH SMALL MOLECULES

High-grade brain tumours are characterized by inter- and intratumour heterogeneity and remain incurable despite current multi-modality treatment. The cellular aggressiveness within brain tumours includes tumour cell invasion of healthy brain tissue, resistance to conventional therapy, and greatly enhanced growth potential. This has been attributed to undifferentiated/stem cell-like features and clonal expansion under therapeutic pressure. The evolving notion of cancer cell plasticity implies that tumour cells may alter their phenotype both randomly and in response to external cues. In this context, we aim to elucidate the molecular mechanisms regulating glioma cell fate. We investigate selective small molecule-induced phenotypic changes such as ‘forced’ differentiation, surface-molecule expression, neurite outgrowth, autophagy, and apoptosis using patient-derived glioma models. Notably, these models display variability in cellular stemness/differentiation characteristics as well as glioma subtype-related classifiers. We therefore further analyse these small molecule-induced phenotypes at the single cell level using gene expression analysis. In addition to chemical/genetic-inspired approaches in vitro, we evaluate the tumour growth and invasion potential of glioma cell phenotypes in vivo. Together, these approaches have revealed molecular vulnerabilities (for example the TACC3-ARNT and HIF axis) that are required for aggressive glioma cell behaviour and may be pharmacologically exploitable for combination therapy.