Inducible mucosa-like differentiation of head and neck cancer cells drives the epigenetically determined loss of cell malignancy
Abstract 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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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 14. Dez. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Oppel, Felix [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2023.06.30.547265 |
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| PPN (Katalog-ID): |
XBI040090167 |
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| 245 | 1 | 0 | |a Inducible mucosa-like differentiation of head and neck cancer cells drives the epigenetically determined loss of cell malignancy |
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| 520 | |a Abstract 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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| 700 | 1 | |a Gendreizig, Sarah |4 aut | |
| 700 | 1 | |a Martinez-Ruiz, Laura |4 aut | |
| 700 | 1 | |a Florido, Javier |4 aut | |
| 700 | 1 | |a López-Rodríguez, Alba |4 aut | |
| 700 | 1 | |a Pabla, Harkiren |4 aut | |
| 700 | 1 | |a Loganathan, Lakshna |4 aut | |
| 700 | 1 | |a Hose, Leonie |4 aut | |
| 700 | 1 | |a Kühnel, Philipp |4 aut | |
| 700 | 1 | |a Schmidt, Pascal |4 aut | |
| 700 | 1 | |a Schürmann, Matthias |4 aut | |
| 700 | 1 | |a Neumann, Judith Martha |4 aut | |
| 700 | 1 | |a Viyof Ful, Flavian |4 aut | |
| 700 | 1 | |a Scholtz, Lars Uwe |4 aut | |
| 700 | 1 | |a Ligum, Dina |4 aut | |
| 700 | 1 | |a Brasch, Frank |4 aut | |
| 700 | 1 | |a Niehaus, Karsten |4 aut | |
| 700 | 1 | |a Escames, Germaine |4 aut | |
| 700 | 1 | |a Busche, Tobias |4 aut | |
| 700 | 1 | |a Kalinowski, Jörn |4 aut | |
| 700 | 1 | |a Goon, Peter |4 aut | |
| 700 | 1 | |a Sudhoff, Holger |4 aut | |
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