Modeling glioblastoma growth patterns and their mechanistic origins

Sammanfattning: Glioblastoma (GBM) is the most common and aggressive primary brain cancer. GBM cells migrate away from the primary lesion and invade healthy brain tissue. The invading cells escape surgical resection, radiotherapy and develop resistance to chemotherapy. Consequently, despite treatment, recurrence is inevitable, and survival is only 14 months. For this purpose, we conducted four studies where we integrated experimental data from extensive patient material with image analysis and mathematical modeling.In study 1, we developed a tool, TargetTranslator, integrating different data modalities to identify new treatments. We implemented an image analysis pipeline to validate our results using a deep artificial neural network to quantify neuroblastoma cell differentiation.In study 2, we integrated the zebrafish and image analysis from study 1 to develop a high-throughput in vivo assay. Zebrafish were orthotopically injected with GBM cells, and each fish's tumor growth and vital status were automatically measured. We characterized the in vivo proliferation rate, survival, and treatment response to the drug marizomib for several patient-derived cell cultures. Light-sheet imaging also revealed two distinct growth types. The first set of cell cultures grew as bulk tumors, whereas the second set invaded vasculature as single cells.In study 3, we used the image analysis from study 1, coupled with an agent-based model to estimate in vitro cell migration and proliferation from single end-point images. The method was validated by a time series data set and applied to a large high-content drug screen of GBM cells. We identified three promising candidates for reducing GBM cell migration. The method can estimate migration on any end-point images of adherent cells without any additional experimental cost.Study 4 characterized the growth and invasive patterns of 45 patient-derived GBM cell cultures in orthogonal mouse xenografts. We found that up to four independent axes of variation could describe the phenotypes and were associated with distinct transcriptomic pathways. The transcriptomic pathways were in part associated with common genomic alterations and subtypes in GBM. We further identified a particularly aggressive GBM phenotype.In conclusion, this thesis was interdisciplinary and aimed to measure survival, invasion, and morphology from extensive patient material. The work had given us new insight into GBM invasion and growth and developed several scalable models suitable for evaluating new therapies.