Single-cell transcriptomic analyses provide insights into the developmental origins of neuroblastoma.

Neuroblastoma is a pediatric tumor of the developing sympathetic nervous system. However, the cellular origin of neuroblastoma has yet to be defined. Here we studied the single-cell transcriptomes of neuroblastomas and normal human developing adrenal glands at various stages of embryonic and fetal development. We defined normal differentiation trajectories from Schwann cell precursors over intermediate states to neuroblasts or chromaffin cells and showed that neuroblastomas transcriptionally resemble normal fetal adrenal neuroblasts. Importantly, neuroblastomas with varying clinical phenotypes matched different temporal states along normal neuroblast differentiation trajectories, with the degree of differentiation corresponding to clinical prognosis. Our work highlights the roles of oncogenic MYCN and loss of TFAP2B in blocking differentiation and may provide the basis for designing therapeutic interventions to overcome differentiation blocks. A single-cell transcriptomic analysis of neuroblastomas and healthy adrenal glands defines cell types and lineage trajectories during different developmental stages. Comparisons with the transcriptomes of neuroblastoma cells show that their transcriptomes most closely resemble those of developing neuroblasts of the adrenal gland.