Bioprinting of patient-derived heterogeneous renal cell carcinoma organoids for personalized therapy

Abstract Tumor organoids that can accurately recapitulate the pathophysiological characteristics of original tumor are urgently needed for personalized therapy. However, there are few published studies on patient-derived renal cell carcinoma (RCC) heterogeneous organoids for drug testing to account for patient-specific heterogeneous clinical responses, which has significantly impeded research in the field. Traditional RCC organoid technologies involving matrigel droplets require intensive manual manipulation and are hampered by variability, functional immaturity, low throughput, and limited scale. Here, we applied extrusion-based high-throughput bioprinter to rapidly generate heterogeneous RCC organoids with uniform size, realizing batch automated stable construction and quality control. Bioprinted RCC organoids reserved the pathological morphology and gene mutation/expression characteristics of original tumor and demonstrate interorganoid and interpatient heterogeneity even after long-term cultivation, which are suitable for preclinical patient-specific drug screening testing. Finally, we created multicellular assembloids by reconstituting RCC aggregates with stromal components to generate an organized architecture with in vivo-like vascular morphology and spatial tumor microenvironment heterogeneity. Thus, we have demonstrated the wide-ranging biomedical utility of bioprinted organoids in furthering our understanding of the physiological mechanisms of tumors and the development of personalized treatment methods.