A human pluripotent stem cell derived differentiation model for the study of normal and transformed sympathoadrenal progenitors

Embryonic tumors have been considered as developmental disorders resulting from disruption of normal differentiation. Neuroblastoma (NB), is a clinically and genetically heterogeneous childhood cancer which is presumed to arise from sympatho-adrenergic progenitors (SAPs). NB can be classified as a predominantly DNA copy-number driven disease, half of which are high-risk cases with poor prognosis. Current multimodal intensive therapy is only successful in 50% of cases with survivors suffering from severe long-term side effects thus illustrating the urgent need for a better understanding of the biology of NB. Lineage survival-dependency transcription factors (TF's) and core regulatory circuits (CRC) carefully control cell fate decisions and cell identity. The role of the individual transcription factors including SOX11, implicated in this process, is largely unknown. In this project, I propose to apply a recently established human embryonic stem cell (hESC) derived differentiation model towards human sympathoblasts to gain a more in depth understanding of the normal and transformed development of these sympathetic neuronal progenitor cells. In particular, I will focus on the role of the SOX11 transcription factor in these processes. I anticipate that the resulting new insights on NB biology will guide me towards identifying novel therapeutic targets.