Resumen de The role of microenvironment in glioblastoma progression and chemoresistance development
Glioblastoma (GBM) is a highly heterogeneous primary brain tumor, with a very low survival rate. It has been shown recently that the complex tumor microenvironment has an essential role in tumor progression and therapy response. Hence, it is crucial to identify all the components and their interactions, and incorporate them in in vitro models used for GBM studies and therapy development.
The development of new technologies in the last decades ensured progress in both mentioned fields. Different multiomics techniques allow detailed characterization of the patient samples. On the other hand, the evolution of cell culture techniques and fabrication processes enables the creation of more physiological in vitro systems than traditional Petri dish culture (organ on chip).
The main aim of this thesis was to study the role of the microenvironment in the response of GBM to temozolomide (TMZ) treatment. Microfluidic devices, previously developed within the group, were modified to study the impact of oxygen concentration on GBM progression. Hypoxia was shown to be essential for the necrotic core formation and it protected cells from the TMZ effect. Moreover, the microfluidic device design was improved to enable the creation of a more advanced and controllable system.
Furthermore, spheroid culture gave us a valuable model for chemoresistance development studies. After the application of two clinical TMZ treatment cycles, the presence of a population of resistant spheroids was observed. Morphologically, those spheroids were a combination of control and treated spheroids, and they had a specific gene expression pattern.
Last but not least, a new spatial transcriptomics technique was used to characterize better GBM patient samples correlating their gene expression with the histological location. It enabled the identification of differential transcriptomic clusters within apparently homogeneous tissues, confirming the high heterogeneity of this tumor, not only in a morphological aspect but also molecularly.
