Pancreatic organoids as cancer avatars for true personalized medicine

• Patient-derived organoids (PDOs) are in vitro models which faithfully preserve morphological, genetic, and molecular features, as well as intratumoral heterogeneity of the original tumors. • PDO therapeutic profiling accurately reflects real-world parental tumor response. • PDOs hold great potential to advance personalized medicine in pancreatic cancer, by guiding treatment selection. Pancreatic ductal adenocarcinoma (PDAC) is a lethal solid malignancy, rapidly progressing and highly therapeutic resistant, as reflected by its very low five-year overall survival. Despite significant advancements in our understanding of its pathobiology and the molecular mechanisms driving its tumorigenesis, therapeutic options remain limited and yield only modest clinical responses. PDAC is characterized by a high genetic inter and intratumoral heterogeneity that shapes its mutational landscape and affects its response to therapies. Facing the limitations of existing preclinical models, the development of personalized medicine in PDAC has been hampered. Translational pancreatic cancer research has been accelerated by the emergence of patient-derived organoids (PDOs), in vitro models faithfully preserving genetic, transcriptomic, proteomic, and epigenetic features and heterogeneity of the parental tumors. This review presents how PDO models can revolutionize precision oncology in pancreatic cancer by prognosticating tumor response and thereby, assist clinical decision-making. Their potential as a preclinical platform for biomarker and drug discovery, as well as future directions for enhancing the therapy response predictive power of organoid-based systems are also discussed.