Single-cell profiling of peripheral neuroblastic tumors identifies an aggressive transitional state that bridges an adrenergic-mesenchymal trajectory

Peripheral neuroblastic tumors (PNTs) represent a spectrum of neural-crest-derived tumors, including neu-roblastoma, ganglioneuroblastoma, and ganglioneuroma. Malignant cells in PNTs are theorized to intercon-vert between adrenergic/noradrenergic and mesenchymal/neural crest cell states. Here, single-cell RNA -sequencing analysis of 10 PNTs demonstrates extensive transcriptomic heterogeneity. Trajectory modeling suggests that malignant neuroblasts move between adrenergic and mesenchymal cell states via an interme-diate state that we term transitional.Transitional cells express programs linked to a sympathoadrenal development and aggressive tumor phenotypes such as rapid proliferation and tumor dissemination. Among primary bulk tumor patient cohorts, high expression of the transitional gene signature is predictive of poor prognosis compared with adrenergic and mesenchymal expression patterns. High transitional gene expres-sion in neuroblastoma cell lines identifies a similar transitional H3K27-acetylation super-enhancer landscape. Collectively, our study supports the concept that PNTs have phenotypic plasticity and uncovers potential biomarkers and therapeutic targets.

Automated summary

Peripheral neuroblastic tumors (PNTs) exhibit extensive transcriptomic heterogeneity, with malignant neuroblasts transitioning between adrenergic and mesenchymal cell states. Transitional cells, expressing programs related to sympathoadrenal development, are associated with aggressive tumor phenotypes and poor prognosis. The identification of transitional gene expression as a potential biomarker and therapeutic target highlights the phenotypic plasticity in PNTs.