Zebrafish xenograft models as a fast platform for metastasis diagnosis and cisplatin response of head and neck squamous cell carcinoma

Abstract Background Head and neck squamous cell carcinoma (HNSCC) is characterized by clinically undetectable early metastasis and a poor prognosis at locally advanced and recurrent metastatic stages. Platinum‐based resistance remains a major limitation to treatment efficacy. Currently, no reliable biomarkers are available to identify lymph node metastasis or to predict therapeutic sensitivity. Therefore, this study aimed to develop a predictive model to address these clinical challenges. Methods Four cell lines (CAL‐27, FaDu, Leuk1, NOEC) were employed to establish zebrafish cell‐derived xenograft (zCDX) models and assess the differential metastatic potential. Surgical or biopsy samples from, respectively, 20 and 14 HNSCC patients were used for building and validating the zebrafish patient‐derived xenograft (zPDX) models. Cisplatin‐sensitive HNSCC cell lines (CAL‐27 and FaDu) and their cisplatin‐resistant sublines (CAL‐27‐DDP and FaDu‐DDP) were established, and the differential responses to cisplatin were evaluated in both murine and zCDX models. Additionally, to assess the patient‐specific therapeutic efficacy of cisplatin, zPDX models were generated from four patient‐derived surgical specimens and a supplementary biopsy for preliminary validation. Results The zebrafish xenograft model recapitulated the invasive phenotype of the HNSCC cell lines. The model distinguished between metastatic and non‐metastatic disease with high accuracy (AUC = 0.98). It faithfully reproduced the cisplatin sensitivity and resistance patterns identified in corresponding in vitro and murine models. Moreover, it showed strong concordance with patient‐specific cisplatin responses. Conclusions The zPDX model provides a rapid, efficient, clinically applicable platform for predicting metastasis and evaluating platinum‐based therapy responses in HNSCC, facilitating the design of scientifically grounded personalized treatment.