Matrigel/serum-free, high-fidelity patient-derived tumor-like cell clusters as an in vitro platform for large-scale compound screening and chemoresistance prediction in oral cancer

BACKGROUND: Current drug regimens for oral cancer are primarily based on generalized clinical guidelines, lacking a precision medicine strategy to tailor therapies to individual patients. This gap highlights the need for robust humanized models that can accurately reflect tumor characteristics and guide personalized treatment selection. METHODS: We developed patient-derived tumor-like cell clusters (PTCs) for oral cancer, an ex vivo model designed to preserve key tumor features including the immune microenvironment, phenotype, and genotype. Then, a prospective observational clinical validation study (ChiCTR2300075543) was conducted in 42 patients with advanced oral squamous cell carcinoma (OSCC) to evaluate the utility of PTC-guided sensitivity testing for the TPF neoadjuvant chemotherapy regimen (docetaxel, cisplatin, fluorouracil). Additionally, the PTC platform was utilized for high-throughput drug screening, and transcriptomic analysis was performed to identify potential predictive biomarkers. RESULTS: PTCs were generated with a success rate exceeding 97% (161/165) using minimal tissue samples (≥ 10 mg). PTC-guided sensitivity testing for the TPF regimen showed ~90% (34/38) concordance with clinical outcomes in advanced OSCC patients. Moreover, the PTC platform successfully enabled high-throughput drug screening (> 100 compounds within two weeks), facilitating the identification of novel anti-cancer targets. Specifically, transcriptomic analysis revealed that upregulation of MMP13 is highly associated with treatment resistance (Pearson's r = 0.90, P < 0.01). CONCLUSIONS: Our PTC-based platform robustly preserves critical tumor characteristics and demonstrates high concordance with clinical treatment outcomes, making it a valuable tool for selecting personalized therapies in oral cancer. Its capacity for large-scale compound screening also supports novel anti-cancer target discovery. Furthermore, MMP13 emerges as a potential predictive biomarker for treatment resistance. Collectively, this PTC platform represents a transformative precision medicine approach to advance personalized therapy and drug discovery in oral cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: ChiCTR2300075543; registered prospectively on September 7, 2023.