Abstract Head and neck squamous cell carcinoma (HNSCC) is a highly malignant disease with high death rates that have remained substantially unaltered for decades.Therefore, new treatment approaches are urgently needed.Human papillomavirus-negative tumors harbor areas of terminally differentiated tissue that are characterized by cornification.
Dissecting this intrinsic ability of HNSCC cells to irreversibly differentiate into non-malignant cells may have tumor-targeting potential.We modeled the cornification of HNSCC cells in a primary spheroid model and analyzed the mechanisms Quoit underlying differentiation by ATAC-seq and RNA-seq.Results were verified by immunofluorescence using human HNSCC tissue of distinct anatomical locations.
HNSCC cell differentiation was accompanied by cell adhesion, proliferation stop, diminished tumor-initiating potential in immunodeficient mice, and activation of a wound-healing-associated signaling program.Small promoter accessibility increased despite overall chromatin closure.Differentiating cells upregulated KRT17 and cornification markers.
Although KRT17 represents a basal stem cell marker in normal mucosa, we confirm KRT17 VITAMIN A DROPS to represent an early differentiation marker in HNSCC tissue.Cornification was frequently found surrounding necrotic areas in human tumors, indicating an involvement of pro-inflammatory stimuli.Indeed, inflammatory mediators activated the differentiation program in primary HNSCC cells.
In HNSCC tissue, distinct cell differentiation states were found to create a common tissue architecture in normal mucosa and HNSCCs.Our data demonstrate a loss of cell malignancy upon faithful HNSCC cell differentiation, indicating that targeted differentiation approaches may be therapeutically valuable.Moreover, we describe KRT17 to be a candidate biomarker for HNSCC cell differentiation and early tumor detection.