Single-Nucleus Transcriptomes of Lacrimal Gland Adenoid Cystic Carcinoma With Different Growth Patterns.

Abstract

Adenoid cystic carcinoma (ACC) is a biphasic malignant tumor characterized by myoepithelial and luminal differentiation. ACC can undergo high-grade transformation (HGT), presenting poorly differentiated features. We used single-nucleus RNA-sequencing to profile the transcriptomes of three primary lacrimal gland ACCs with different growth patterns. A molecular landscape of tumor epithelial subtypes revealed heterogeneity of ACC. In cribriform tumor, a subset of transitional cells was identified intermediately between myoepithelial and luminal cells along the inferred lineage trajectory; MYB was highly expressed and Wnt signaling was activated. In well-differentiated luminal cells, MYB was downregulated, Notch and FGF pathways were activated with upregulation of KIT. In HGT tumor, Wnt and Notch pathways were suppressed with upregulation of WNT2B and JAG1. The differential activity of key transcriptional factors drives overexpression of key ligands and receptors. HGT suggests a state of developmental ambiguity with dysregulated key signaling cascades that impede cellular differentiation.