Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited therapeutic options and poor prognosis. For translational research, although patient-derived organoids (PDOs) have emerged as powerful platforms for modeling tumor biology and drug response, conventional tissue-derived organoids are often limited by low cellularity, contamination with non-tumor cells, and the invasiveness of tissue sampling. Here, we report the establishment and characterization of fluid-derived organoids (FDOs) from malignant pleural effusion and ascitic fluid of PDAC patients. Compared to tissue-derived PDOs, FDOs were established more rapidly and less invasively, with higher success rates and reduced contamination by non-tumor cells. FDOs retained key histopathological and molecular features of the primary tumor, including KRAS mutations and epithelial marker expression. Holotomography imaging revealed distinct morphological and subcellular phenotypes of fluid-derived cancer organoids, reflecting their divergence from normal organoids as well as temporal changes associated with treatment response and disease progression. In vivo xenograft assays confirmed the tumorigenic potential of FDOs, particularly those derived from advanced disease. Drug screening demonstrated that FDOs harboring KRAS G12D mutations responded to the KRAS inhibitor MRTX1133. Transcriptomic profiling identified a poor prognosis-associated gene signature that conferred gemcitabine resistance by suppressing apoptosis. Collectively, our findings establish FDOs as clinically relevant, minimally invasive, and scalable models that enable personalized therapy and biomarker discovery in PDAC. Citation Format: Hee Seung Lee, Yoo Keung Tae, Sang-Min Kim, Jung-hwan Park, Kyu Min Lim, HyunKi Kim, Jung Hyun Jo. Minimally invasive fluid-derived organoids enable modeling of chemotherapy resistance in pancreatic ductal adenocarcinoma abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr B095.
Lee et al. (2025) studied this question.