Physics of cancer: mechanotransduction in the adaptive response of glioblastoma cells to matrix stiffness

Glioblastoma multiforme (GBM) is an aggressive brain tumor, with no specific early symptoms or apparent cause, for which there is currently no effective prevention or treatment. Only a few drugs for GBM have been introduced in the last 30 years that have slightly improved the prognosis. Recent physicochemical and biological studies of GBM tumor cells and the tumor microenvironment (TME) have shown that the GBM tumor is heterogeneous and has different mechanical properties compared to healthy brain tissue. In addition, the TME has a different chemical composition compared to healthy brain tissue, which in turn results in unique physical traits of the brain extracellular matrix (ECM). This complexity highlights the need for multidisciplinary research to further study the GBM malignant behavior with an aim to develop novel targeted therapies. Physics of cancer is a new multidisciplinary research field in which cancer is studied from a (bio)physical perspective. In this thesis, the influence of matrix stiffness on mechanotransduction and the adaptive response of GBM cells is studied. The possible role of the unfolded protein response (UPR) sensor, endoplasmic reticulum protein kinase (PERK), in mediating mechanotransduction signaling is investigated. Two mechanisms can be distinguished here, namely how cells sense the matrix stiffness (mechanosensation) and later how they adapt to it (mechano-adaptation). Our findings show that PERK plays a role in both mentioned cellular signaling processes. Also, this thesis has a specific look at the development of new gel systems for use in 3D bioprinting to better mimic the microarchitecture of brain tissue