Postnatal Sustentacular Cells as Chromaffin Progenitors and Tumor Cells of Origin in VHL-Related Paragangliomas

The cellular source of chromaffin cell regeneration after birth and its relationship to paraganglioma tumorigenesis remains incompletely defined. Here, we identify a postnatal population of SOX2/SOX10-expressing sustentacular glia-like cells in the organ of Zuckerkandl (OZ) and adrenal gland that give rise to chromaffin cells in vivo . These cells differ transcriptionally from embryonic chromaffin progenitors known as Schwann cell precursors and exhibit a unique progenitor signature. Genetic lineage tracing confirms their postnatal contribution to chromaffin cells, and SOX2 + PHOX2B + transitional cells were observed in both human and mouse OZ and adrenal tissues. Single-nuclei RNA-seq and inferCNA analysis of pheochromocytoma and paraganglioma (PPGL) revealed that while most sustentacular cells exhibit a stromal profile, a subset in VHL-mutated PPGLs harbor the hallmark 3p chromosomal loss shared with chief tumor cells, suggesting a clonal origin. In an additional PPGL, widespread SOX2 expression in PHOX2B + tumor cells supports this hypothesis. Finally, DLK1-NOTCH signaling was predicted as a central regulator of chromaffin–sustentacular communication, suggesting DLK1 fine-tunes chromaffin regeneration via NOTCH inhibition and may represent a therapeutic target in PPGL.