Genomic and Single-Cell Analyses Characterize Patient-Derived Tumor Organoids to Enable Personalized Therapy for Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) remains a ITH program was associated with cisplatin resistance and poor significant health burden because of tumor heterogeneity and patient survival. Functional analyses identified amphiregulin as a treatment resistance, emphasizing the need for improved biolog- potential regulator of the hybrid epithelial–mesenchymal state. ical understanding and tailored therapies. In this study, we en- Moreover, amphiregulin contributed to cisplatin resistance via EGFR rolled 31 patients with HNSCC for the establishment of patient- pathway activation, corroborated by clinical samples. In summary, derived tumor organoids (PDO), which faithfully maintained the HNSCC PDOs serve as reliable and versatile models, offer predictive genomic features and histopathologic traits of the primary tumors. insights into ITH programs and treatment responses, and uncover Long-term culture preserved key characteristics, affirming PDOs potential therapeutic targets for personalized medicine. as robust representative models. PDOs demonstrated predictive capability for cisplatin treatment responses, with ex vivo drug Significance: Profiling of patient-derived organoids uncovers sensitivity correlating with patient outcomes. Bulk and single-cell intertumoral heterogeneity and a hybrid epithelial–mesenchymal RNA sequencing unveiled molecular subtypes and intratumor transition program conferring cisplatin resistance and highlights transcriptional heterogeneity (ITH) in PDOs, paralleling patient amphiregulin as a regulator of cellular plasticity and potential tumors. Notably, a hybrid epithelial–mesenchymal transition–like therapeutic target for HNSCC treatment.