Development of patien-derived cancer models of pediatric brain tumours
Pediatric high-grade brain tumors are, up until today, the main cause of cancer-related death in children. This is explained by differences between- and within the tumors themselves, so-called “inter-and intratumoral heterogeneity”, which are exhibited on several levels. Heterogeneity is present in the genetic material and in the modifications on the DNA and DNA-related proteins that affect the expression of genes (“epigenetic”), creating many subgroups. In addition, the non-tumoral cells in and surrounding the tumor are variable and influence tumor cells. As these tumors are so diverse, they also show variations in their responses to treatment (“drug response heterogeneity”). In this project, I will provide deeper insights in these tumors using state-of-the-art methods to determine the different levels of heterogeneity. This will be done at the highest resolution, meaning the single cell, determining different parameters at the same time. A newly implemented method will be used to assess the spatial heterogeneity of the tumors, including the non-tumoral cells. To investigate drug response heterogeneity, I will use existing and novel patient-derived models. After an in dept characterization of heterogeneity at the different levels, these models will be treated with various therapeutics. “Mass cytometry by time-of-flight” will be used to determine the drug response heterogeneity on the single-cell level.