Exploring Principles of the Interplay Between Tumour Initiating Cells and the Endothelial Component in Glioblastoma

Efficient targeting of multiple components of a tumour might be a successful strategy in aggressive types of cancer such as glioblastoma (GBM), which remains the most common and malignant primary brain tumour with an extremely poor patient survival of less than 15 months. The significant therapeutic challenge posed by GBM stems from its genetic and phenotypic heterogeneity fueled by multiple components of the tumour biology including aggressive and treatment-resistant populations of tumour initiating cells (TICs) and high levels of angiogenesis contributing to tumour evolution, evasion of therapy and recurrence. TICs, which are at the source of GBM patient relapse, thrive in the niches close to the blood vessels where they interact with endothelial cells (ECs), exit the cell cycle, and evade therapies. Targeted antiangiogenic drugs, preventing GBM cells from recruiting new blood vessels, are only effective in 50% of patients and display temporary effectiveness due to acquired secondary resistance by the tumour. Thus, there is an urgent need for new and effective therapeutic strategies. This project will explore the TIC-EC interplay and its role in propagating tumour aggressiveness and therapy resistance. This project will investigate the impact of ECs on the aggressive characteristics of individual, specific populations of TICs using GBM patient-derived systems, including 3D organoid models and zebrafish patient-derived xenografts (PDXs). Elucidating the details of specific cellular populations of aggressive TICs with dependence on the EC component will contribute to the identification of improved therapeutic targets and personalized approaches for treatment of patients with GBM.