Single-nucleus RNA sequencing reveals that canine acanthomatous ameloblastoma is marked by a unique population of neuronal-like epithelial cells

Across ~205,000 nuclei, we identified major epithelial, immune, endothelial, and mesenchymal populations, as well as two epithelial subtypes uniquely enriched in CAA. The CAA-specific keratinocytes exhibited a neuronal-like expression program defined by synaptic regulators, KRAS-associated signaling pathways, and markedly elevated expression of PEG3, ERBB4, GABRB1, MAGI2, and CASK. We corroborated these findings using both bulk RNA-seq and qPCR.

At the protein level, using immunohistochemistry, the transcription factor PEG3 was strongly detected and shown to localize to the nucleus of CAA epithelial cells but not COSCC or healthy gingiva. Together, these findings reveal a previously unrecognized neuroepithelial cell state that defines CAA, distinguishes it from COSCC, and may reflect unique cell signaling circuitry with potential diagnostic and therapeutic relevance.