Inducible mucosa-like differentiation of head and neck cancer cells drives the epigenetically determined loss of cell malignancy
Oppel F, Gendreizig S, Martinez-Ruiz L, Florido J, López-Rodríguez A, Pabla H, Loganathan L, Hose L, Kühnel P, Schmidt P, Schürmann M, et al. (2023)
bioRxiv.
;
Martinez-Ruiz, Laura;
Florido, Javier;
López-Rodríguez, Alba;
Pabla, Harkiren;
Loganathan, Lakshna;
Hose, LeonieUniBi ;
Kühnel, PhilippUniBi ;
Schmidt, PascalUniBi;
Schürmann, MatthiasUniBi;
Neumann, Judith MarthaUniBi
Alle
**Background**
Human papillomavirus-negative 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 striking tumor-targeting potential.
**Methods**
We modeled the cornification of HNSCC cells in a primary spheroid model and analyzed the mechanisms underlying differentiation by RNA-seq and ATAC-seq. Results were verified by immunofluorescence using human HNSCC tissue of distinct anatomical locations.
**Results**
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 to represent an early differentiation marker in HNSCC tissue and dysplastic mucosa. Cornification was observed to frequently surround necrotic and immune-infiltrated areas in human tumors, indicating an involvement of pro-inflammatory stimuli. Indeed, inflammatory mediators were found to activate the HNSCC cell differentiation program.
**Conclusions**
Distinct cell differentiation states create a common tissue architecture in normal mucosa and HNSCCs. Our data demonstrate a loss of cell malignancy upon 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.
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