Incorporation of human iPS cell-derived stroma creates a pancreatic cancer organoid with heterogeneous cancer-associated fibroblasts [scRNA-Seq]. Incorporation of human iPS cell-derived stroma creates a pancreatic cancer organoid with heterogeneous cancer-associated fibroblasts [scRNA-Seq]

The aggressiveness of pancreatic ductal adenocarcinoma (PDAC) is affected by a tumor microenvironment (TME). In this study, to recapitulate 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 air–liquid interface. FPCOs were further induced to resemble two distinct parts of a PDAC tissue. Owing to various types of cancer associated fibroblasts (CAFs) derived from hiPSCs, the TME consisted of abundant extracellular matrix proteins, which likely conferred strong drug resistance to PDAC cells in one type of FPCOs. Because of re-proliferation capacity of PDAC cells after anticancer drug treatment, the other FPCO is the first culture system for investigating PDAC recurrence. Introducing hiPSC technology, we have created, for the first time, the PDAC organoids representing the heterogeneity of PDAC tissue, a potential platform for screening anticancer drugs. Overall design: Two types of fused pancreatic cancer organoid(FPCO) generated by patiend-derived pancreatic cancer organoids(PCOs), hiPSC-derived mesenchymal cells(hiPSC-MC) and vascular endothelial cells(hiPSC-EC).

胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）的侵袭性受肿瘤微环境（tumor microenvironment, TME）影响。本研究为体外重现PDAC的肿瘤微环境，将患者来源的PDAC细胞与人诱导多能干细胞（human induced-pluripotent stem cells, hiPSCs）分化得到的间充质细胞与血管内皮细胞共培养，在气液界面体系中构建了融合性胰腺癌类器官（fused pancreatic cancer organoid, FPCO）。随后，我们进一步诱导FPCO模拟PDAC组织的两种不同组分。由于hiPSCs分化产生的多种癌相关成纤维细胞（cancer associated fibroblasts, CAFs），其中一类FPCO的TME富含细胞外基质蛋白，这可能使其内部的PDAC细胞获得较强的药物耐药性。另一类FPCO可模拟抗肿瘤药物处理后PDAC细胞的再增殖能力，是首个用于研究PDAC复发的培养体系。本研究借助hiPSC技术，首次构建了能够体现PDAC组织异质性的PDAC类器官，为抗肿瘤药物筛选提供了潜在研究平台。整体实验设计：通过患者来源的胰腺癌类器官（patient-derived pancreatic cancer organoids, PCOs）、hiPSC来源的间充质细胞（hiPSC-derived mesenchymal cells, hiPSC-MC）以及血管内皮细胞（hiPSC-EC），构建了两类融合性胰腺癌类器官（FPCO）。