Incorporation of human iPSC-derived stromal cells creates a pancreatic cancer organoid with heterogeneous cancer-associated fibroblasts.

The aggressiveness of pancreatic ductal adenocarcinoma (PDAC) is affected by the tumor microenvironment (TME). In this study, to recapitulate the PDAC TME ex vivo , we cocultured patient-derived PDAC cells with mesenchymal and vascular endothelial cells derived from human induced pluripotent stem cells (hiPSCs) to create a fused pancreatic cancer organoid (FPCO) in an air-liquid interface. FPCOs were further induced to resemble two distinct aspects of PDAC tissue. Quiescent FPCOs were drug resistant, likely because the TME consisted of abundant extracellular matrix proteins that were secreted from the various types of cancer-associated fibroblasts (CAFs) derived from hiPSCs. Proliferative FPCOs could re-proliferate after anticancer drug treatment, suggesting that this type of FPCO would be useful for studying PDAC recurrence. Thus, we generated PDAC organoids that recapitulate the heterogeneity of PDAC tissue and are a potential platform for screening anticancer drugs. [Display omitted] • Fused pancreatic cancer organoids (FPCOs) recapitulate CAF heterogeneity • Two types of FPCOs resemble distinct parts of primary PDAC tumor tissue • Localization of myCAFs correlated with the malignant phenotype of PDAC cells • FPCOs show chemoresistance or reproliferation potential after drug treatment Takeuchi et al. generated a fused pancreatic cancer organoid (FPCO) by co-culturing patient-derived cancer cells with endothelial cells and mesenchymal cell-derived human induced pluripotent stem cells (hiPSCs). FPCOs resembled two distinct parts of PDAC tissue, and they reproduced the tumor microenvironment, including the heterogeneity of CAFs. [ABSTRACT FROM AUTHOR]