Glioblastoma (GB) is the most common and aggressive form of primary malignant tumors in the central nervous system. The prognosis of GB patients is generally poor, on average around 15 months after diagnosis, as even the most intensive treatments rarely lead to a significant improvement in survival.
GB is a highly heterogeneous tumor in which GB stem cells (GSCs) play an important role. The 'Unfolded Protein Response (UPR)' is a molecular mechanism that ensures the maintenance of protein homeostasis in the cell and is activated under stressful conditions, such as viral infections, nutrient deficiency or oxygen deficiency (hypoxia), leading to endoplasmic reticulum (ER) stress. The activation of the ER stress sensors PERK, IRE1 and ATF6 in cells is the first step in the UPR and ultimately determines whether a cell survives or dies. In addition, recent research shows that the UPR sensors PERK and IRE1 have other functions, including regulating the dynamics of the cytoskeleton.
The primary aim of the research in this thesis of Liang Dong is to investigate both the canonical (classical UPR) and non-canonical (not in UPR) functions of PERK, as well as the role of PERK in the regulation of GSCs and as a possible therapeutic target. Specifically, we investigated the adaptation of GSCs to increasing extracellular matrix (ECM) stiffness, PERK-dependent molecular mechanisms regulating GSC adhesion and differentiation, and the possibility of using PERK as a therapeutic target in GB.
