The identification of strongly HIF-2a positive, neural crest-like tumor cells located perivascularly in neuroblastoma specimens and the observation that high HIF-2a protein levels in neuroblastoma correlate to disseminated and aggressive disease, suggest that HIF-2 is a potential marker and treatment target of neuroblastoma tumor stem/initiating cells. The gain-of-function mutations in HIF2A found in sporadic paragangliomas and pheochromocytomas (PPGLs) show that HIF2A is a bona fide oncogene and that the resulting pseudohypoxic phenotype is important for the oncogenic process leading to an immature, stem cell-like phenotype and metastatic growth. Our aim is to inhibit HIF-2 directly or indirectly at different oxygen tensions. We hypothesize that inhibition of HIF-2 will result in impaired metastatic growth and a more mature sympathetic phenotype. An important tool in this project is our orthotopic neuroblastoma patient-derived xenograft (PDX) model, as these tumors metastasize to all relevant clinical sites including bone marrow. The PPGLs are generally localized tumors that can be treated by surgery. However, the aggressive forms cannot be identified at the time of diagnosis and we aim to identify a gene marker signature of advanced tumors. Currently there is no available treatment for advanced PPGL and no human PPGL cell lines or animal models are available for pre-clinical drug testing. We therefore aim to establish orthotopic PDX models for these very rare tumors.