Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Teutoburger Str. 50, 33604, Bielefeld, Germany.
Institute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada, Granada, Spain.
Cell Death Dis. 2024 Jul 19;15(7):517. doi: 10.1038/s41419-024-06867-4.
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.
头颈部鳞状细胞癌（HNSCC）是一种高度恶性的疾病，几十年来死亡率一直保持在约 50%。迫切需要新的肿瘤靶向策略，之前的一份报告表明，HPV 阴性 HNSCC 细胞的触发分化可带来治疗益处。使用患者来源的肿瘤细胞，我们从两名患者中创建了类似的 HPV+肿瘤细胞的 HNSCC 分化模型。我们观察到在分化细胞培养条件下恶性特征丧失，包括细胞形态不规则增大、Ki67 下调导致细胞周期停滞以及细胞活力降低。RNA-Seq 显示出肌样分化，肌纤维组装标志物上调。分化和未分化的原发性 HPV+ HNSCC 细胞的免疫荧光染色证实了这些标志物的上调，并形成了类似于成肌细胞系细胞的平行肌动蛋白纤维。此外，HPV+肿瘤组织的免疫荧光显示出共同表达肌纤维组装标志物、HPV 替代标志物 p16 和应激相关基底角质形成细胞标志物 KRT17 的细胞区域，表明观察到的体外肌样分化发生在人体组织中。我们是第一个报告癌细胞可以发生触发的肌样分化的，我们的研究表明，HPV+ HNSCC 的靶向分化可能具有治疗价值。
