Human papillomavirus-associated head and neck squamous cell carcinoma cells lose viability during triggered myocyte lineage differentiation Gendreizig, Sarah Martínez Ruiz, Laura López Rodríguez, Alba Pabla, Harkiren Hose, Leonie Brasch, Frank Busche, Tobias Escames Rosa, Germaine Sudhoff, Holger Uwe Scholtz, Lars Todt, Ingo Oppel, Felix Head and neck squamous cell carcinoma (HNSCC) is a highly malignant disease, and death rates have remained at approximately 50% for decades. New tumor-targeting strategies are desperately needed, and a previous report indicated the triggered differentiation of HPV-negative HNSCC cells to confer therapeutic benefits. Using patient-derived tumor cells, we created a similar HNSCC differentiation model of HPV+ tumor cells from two patients. We observed a loss of malignant characteristics in differentiating cell culture conditions, including irregularly enlarged cell morphology, cell cycle arrest with downregulation of Ki67, and reduced cell viability. RNA-Seq showed myocyte-like differentiation with upregulation of markers of myofibril assembly. Immunofluorescence staining of differentiated and undifferentiated primary HPV+ HNSCC cells confirmed an upregulation of these markers and the formation of parallel actin fibers reminiscent of myoblast-lineage cells. Moreover, immunofluorescence of HPV+ tumor tissue revealed areas of cells co-expressing the identified markers of myofibril assembly, HPV surrogate marker p16, and stress-associated basal keratinocyte marker KRT17, indicating that the observed myocyte-like in vitro differentiation occurs in human tissue. We are the first to report that carcinoma cells can undergo a triggered myocyte-like differentiation, and our study suggests that the targeted differentiation of HPV+ HNSCCs might be therapeutically valuable. 2024-10-08T11:13:16Z 2024-10-08T11:13:16Z 2024-06-25 journal article Gendreizig, S. et. al. Cell Death Dis 15, 517 (2024). [https://doi.org/10.1038/s41419-024-06867-4] https://hdl.handle.net/10481/95688 10.1038/s41419-024-06867-4 eng http://creativecommons.org/licenses/by/4.0/ open access Atribución 4.0 Internacional SpringerLink