Sympathoadrenal Lineage Plasticity Drives Intratumoral Heterogeneity in Paraganglioma, Neuroblastoma and Composite Tumors Following KIF1Bβ-NF1 Loss

Abstract Neuroblastoma (NB) and paraganglioma (PPGL) arise from the sympathoadrenal lineage and often occur in the adrenal medulla, however their developmental relationship and the mechanisms underlying their heterogeneity remain unknown. Using a genetically engineered mouse model, we show that loss of KIF1Bβ, a candidate 1p36 tumor suppressor, cooperates with Nf1 loss in tumorigenesis and cell-state reprogramming within the sympathoadrenal lineage, giving rise to paraganglioma, neuroblastoma, and composite tumors. Single-cell transcriptomics and trajectory inference across developmental, pre-neoplastic, and tumor stages, reveal chromaffin-toward-neuroblast reprogramming through developmental intermediates. Spatial transcriptomic analyses demonstrate that these transitions occur among spatially organized tumor cell states and are accompanied by spatially restricted re-expression of embryonic neurodevelopmental gene programs. Spatial profiling of human PPGL reveals chromaffin-like, neuroblast-like, and connecting progenitor states arranged in spatial proximity, indicating that chromaffin-neuroblast plasticity is conserved in human tumors. These findings define a developmental mechanism of tumor plasticity, establish KIF1Bβ as a bona fide tumor suppressor in vivo, and provide a mechanistic framework for sympathoadrenal plasticity that enables the emergence of neuroblast-like states in paraganglioma. Competing Interest Statement The authors have declared no competing interest.