Head and neck cancer cells terminally differentiate reflecting their tissue of origin: a rationale for differentiation therapies

Oppel, F.; Gendreizig, S.; Martinez-Ruiz, L.; Florido, J.; Lopez-Rodriguez, A.; Pabla, H.; Loganathan, L.; Hose, L.; Kuehnel, P.; Schmidt, P.; Schuermann, M.; Neumann, J. M.; Viyof Ful, F.; Scholtz, L. U.; Ligum, D.; Brasch, F.; Niehaus, K.; Escames, G.; Busche, T.; Kalinowski, J.; Goon, P.; Sudhoff, H.

doi:10.1101/2023.06.30.547265

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bioRxiv · 10.1101/2023.06.30.547265

Head and neck cancer cells terminally differentiate reflecting their tissue of origin: a rationale for differentiation therapies

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Abstract

BackgroundHuman 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. MethodsWe 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. ResultsHNSCC 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. ConclusionsDistinct 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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Oppel, F., Gendreizig, S., Martinez-Ruiz, L., Florido, J., Lopez-Rodriguez, A., Pabla, H., Loganathan, L., Hose, L., Kuehnel, P., Schmidt, P., Schuermann, M., Neumann, J. M., Viyof Ful, F., Scholtz, L. U., Ligum, D., Brasch, F., Niehaus, K., Escames, G., Busche, T., Kalinowski, J., Goon, P., Sudhoff, H.. 2023-07-03. Head and neck cancer cells terminally differentiate reflecting their tissue of origin: a rationale for differentiation therapies. https://doi.org/10.1101/2023.06.30.547265

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