From Single Cells to 3D Cultures: Fundamental research on Neuroblastoma and Medulloblastoma

Abstract

Pediatric cancer is rare and encompasses many cancer entities. It is the lead cause of childhood mortality, even though there has been an increase in overall survival over the years. This increase in survival was in part possible due to fundamental research on tumor biology, as well as testing on experimental models. In this thesis, we aimed to apply fundamental research techniques to better understand neuroblastoma and medulloblastoma biology and to develop new model systems that can help to identify novel treatments. We discuss a multi-cell-of-origin hypothesis for neuroblastoma, evidence based on both clinical and molecular studies. Through single cell sequencing of the developing murine adrenal gland we provide an in-depth depiction of the neural crest derivatives. The gene signature of the Schwann cell precursor (SCP) could be used to identify neuroblastoma tumors that were associated with a less severe disease phenotype. In a subsequent study we optimized the SCP signature and showed that, in a cohort of Princess Máxima Center patients, the SCP signature can stratify patients in groups with different prognoses. For medulloblastoma, we present a novel approach for growing medulloblastoma patient material in 3D, called medulloblastoma tumoroids. We used these tumoroids to test the efficacy of drugs currently in clinical trials for medulloblastoma. Finally, we speculate on the importance of fundamental research in pediatric oncology for the development of new treatments and risk stratification.