Title : High-throughput drug screening using 3D bioprinted human skin models to identify therapeutic candidates for melanoma and squamous cell carcinoma
Abstract:
Melanoma and squamous cell carcinoma are among the most common skin cancers worldwide, with rising incidence and significant clinical impact. To enhance the translational relevance of preclinical drug discovery, we developed high-throughput, three-dimensional (3D) bioprinted human skin cancer models for compound screening in 96 well format. The platform incorporates fluorescently labeled human fibroblasts, keratinocytes, and either A375 melanoma or A431 squamous cell carcinoma cells, enabling concurrent evaluation of tumor-selective efficacy and host tissue toxicity. Using a tiered screening workflow, 971 small molecules from the NCATS MIPE 5.0 library were tested across both tumor types. Compounds were prioritized based on selective reduction of cancer cell viability while preserving fibroblast viability, resulting in the identification of 18 melanoma-selective and 8 squamous cell carcinoma–selective hit compounds with diverse mechanisms of action. Across both cancer models, hit compounds exhibited enhanced maximal responses and altered potency in 3D tissues compared with conventional 2D cultures, underscoring the improved sensitivity and physiological relevance of the 3D system. These findings demonstrate that bioprinted 3D skin cancer models provide a robust and scalable platform for identifying therapeutically promising compounds across multiple skin cancer types that may be overlooked by traditional screening approaches.
