Neuroblastoma plasticity during metastatic progression stems from the dynamics of an early sympathetic transcriptomic trajectory
Despite their indisputable importance in neuroblastoma (NB) pathology, knowledge of the bases of NB plasticity and heterogeneity remains incomplete. They may be rooted in developmental trajectories of their lineage of origin, the sympatho-adrenal neural crest. We found that implanting human NB cells in the neural crest of the avian embryo allows recapitulating the metastatic sequence until bone marrow involvement. Using deep single cell RNA sequencing, we characterized transcriptome states of NB cells and their dynamics over time and space, and compared them to those of fetal sympatho-adrenal tissues and patient tumors and bone marrow samples. Here we report remarkable transcriptomic proximities restricted to an early sympathetic neuroblast branch that co-exist with phenotypical adaptations over disease progression and recapitulate intratumor and interpatient heterogeneity. Combining avian and patient datasets, we identified a list of genes upregulated upon bone marrow involvement and associated with growth dependency, validating the relevance of our multimodal approach. Overall design: IGR-N91::GFP cells were harvested before cells engraftment and from chick embryos using a fluorescence stereomicroscope. Tumor cells were dissected out from E5 chick embryos in sympatho-adrenal tissues and from E14 chick embryos at different localizations: primary tumor sites (adrenal medulla, ADR, and sympathetic ganglia, SG), secondary metastatic site (bone marrow, BM), and NB cells on spreading routes (dorsal aorta, AOR, and embryonic peripheral nerves, PN).