Progress and challenges in the development of advanced pancreatic cancer organoids

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis and rising incidence. Late detection and limited responsiveness to standard treatment translates into a 5-year overall survival of less than 12%. The pathology contributes to a desmoplastic tumor microenvironment that creates a physical barrier, leading to a dense, hypoxic environment that promotes further tumorigenesis, limited immunogenicity, and chemoresistance, resulting in a still significant translational gap in PDAC research. Feasible techniques to further elucidate tumorigenesis are indispensable because of the frequently limited predictive value of current preclinical models. PDAC organoids offer a powerful tool that can be rapidly generated from resected tumors and biopsies. This review summarizes the current technical and scientific knowledge and highlights the importance of the tumor microenvironment, the use of realistic oxygen conditions, and the role of the hypoxia-inducible factors. Additionally, various protocols based on different media and scaffolds are displayed, and it is illustrated how PDAC organoids can help to improve both diagnosis and treatment options. Finally, critical bottlenecks in modeling PDAC tumor-stromal interactions are identified, and integrated co-culture platforms are proposed as a promising solution for translational applications.