Role of WDR66 in Stemness, Therapy Resistance and Tumor microenvironment modulation in Head and Neck Cancer

Head and neck cancer comprises a variety of malignant tumors affecting regions such as the oral cavity, pharynx, larynx, paranasal sinuses, nasal cavity and salivary glands. These tumors are highly heterogeneous, making it difficult to identify specific biomarkers and effective treatments, increasing mortality and recurrence rates. Databases analyzed to identify genes with altered expression in tumor tissue showed WDR66 able predict prognosis and survival, in HNSCC, but whose involvement in tumorigenesis is unknown. High WDR66 expression was associated with a worse prognosis, although its overexpression did not significantly alter basic tumor properties in cancer cells in vitro or in vivo. However, we observed an increase in pluripotency factors (OCT3/4, SOX2, KLF4, LIN28), resistance to chemotherapies and a decrease in apoptosis. Consistently, decreasing WDR66 expression using CRISPR showed a reduction in tumorsphere formation, lower expression of pluripotency-related genes, decreased cell migration, and increased sensitivity to cisplatin. These effects were more pronounced in vivo, suggesting a relevant role of WDR66 in the tumor microenvironment. The medium conditioned by cells overexpressing WDR66 promoted migration, maintained the stem cell phenotype, and inhibited immune differentiation, harboring soluble factors involved in progression and metastasis. In this media, we identified several cytokines and growth factors related to inflammation and immune system modulation. In conclusion, WDR66 emerges as a potential biomarker of poor prognosis and a possible predictor of response to immunotherapy, given its impact on cellular pluripotency, treatment resistance and modification of the tumor microenvironment in head and neck cancer.