Spatially organized developmental cell states link paraganglioma and neuroblastoma through chromaffin-neuroblast plasticity

Zhu, J., Li, W., Paramonov, V., Cui, P., Poltorachenko, V., Bullova, P., Arceo, M., Plescher, M., Stada, J., Hose, K. S., et al.

10.64898/2026.04.07.715303 · was preprinted

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Abstract

Neuroblastoma (NB) and paraganglioma (PPGL) arise from the sympathoadrenal lineage, yet their developmental relationship and heterogeneity remain unclear. Single-cell and spatial transcriptomics revealed shared, spatially organized developmental states, including populations characteristic of the other tumor type, chromaffin-like cells in NB and neuroblast-like cells in PPGL and hybrids co-expressing adjacent states. Deconvolution of an independent PPGL cohort associated metastatic disease most strongly with chromaffin hybrid states, alongside connecting progenitor-like, cycling neuroblast, and early chromaffin identities, whereas non-metastatic tumors were enriched for differentiated late chromaffin identities. In mice, combined loss of the candidate 1p36 tumor suppressor KIF1B{beta} and NF1 recapitulates these developmental architectures by prolonging developmental plasticity, reactivating embryonic neurogenic programs, and driving chromaffin-to-neuroblast transitions generating pheochromocytoma, neuroblastoma and composite tumors. Mouse tumors contained discrete spatial domains of developmental and neoplastic states that mirrored those in human PPGL. Together, our findings establish chromaffin-neuroblast plasticity as a mechanism of sympathoadrenal tumor heterogeneity and identify hybrid developmental states as a potential indicator of plasticity associated with metastatic PPGL.

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biorxiv v2 2026-08-14 source ↗

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