ITGA6⁺ epithelial cell-associated bone invasion in head and neck squamous cell carcinoma: Single-cell sequencing reveals epithelial-mesenchymal transition as a major factor.

Bone invasion is a strong indicator of a poor prognosis in head and neck squamous cell carcinoma (HNSCC), although the underlying mechanisms are still unclear. Due to the limited resolution of bulk sequencing, the specific malignant epithelial cell (EPC) subpopulation responsible for bone invasion and its regulatory network have long been unclear. We developed a comprehensive cellular atlas of EPCs in bone-invasive HNSCC using single-cell transcriptome sequencing, and we carefully examined their subpopulation heterogeneity, functional states, and transcriptional regulatory networks. The primary subpopulation found to be associated with bone invasion was the C2 ITGA6⁺ EPC. Mechanistically, these intermediate transitional cells may facilitate bone invasion via an epithelial-mesenchymal transition program controlled by TP63, with connections between the tumor microenvironment regulated by LAMININ and EPHB signaling. This discovery may help develop customized treatment options by providing a novel single-cell-resolution viewpoint on the molecular associations underlying bone-invasive HNSCC.