Establishment of validation models and anti-cancer drug target discovery for investigation of GBM invasion

Abstract

Glioblastoma mutiforme (GBM), the most aggressive primary malignant brain tumor, has infiltrative character-istics and highly heterogeneous cell populations in the tumor microenvironments. Due to the greatly diffusive behaviors, definitive surgical resection is precluded, and diverse cell components cause radio- and chemo-resistance. Therefore, recurrence occurs frequently, and overall survival is quite short. In this study, I aimed to investigate GBM cell behaviors, specifically focusing on the invasive characteristics. To investigate GBM cell migration and invasion induced by interaction with the tumor microenvironment, I constructed in vitro and in vivo validation models to discover new biomarkers for anti-invasion drugs at the clinical level. GBM cells migrate along preexisting thin microstructures and invade surrounding normal tissues. I established the biomimetic cell culture platform to mimic these structural and mechanical cues in tumor micro-environments of GBM as well as to mimic striated muscle structures for VSMC phenotypic modulation in Part 2. The biomimetic system induced cytomorphological changes and migration along the pattern. GSCs, a subpopulation of tumor stromal cells with self-renewal properties and pluripotency, exhibit unique behaviors near microvessels, otherwise known as the “perivascular niche”. However, it has not been identified whether GSCs migrate along microvessels like tumor cells. To monitor the GSC behaviors near the vessels, I constructed two intravital animal models for a GSC invasion study in Part 3. With these animal mod-els, I observed migration of the GSCs along the microvasculature and different adaptations in distinguished microenvironments. In Part 4, I tried to discover new anti-cancer drug targets by using multi-step computational analysis of GBM patient data obtained from public databases, and then, verify the involvement of the candidate genes in cell migration ability in vitro. Collectively, these three independent studies could be integrated into a systemic investigation of GBM invasion, from target discovery to in vitro and in vivo validation.