Incorporation of human iPSC-derived stromal cells creates a pancreatic cancer organoid with heterogeneous cancer-associated fibroblasts
Kenta Takeuchi,
Shunsuke Tabe,
Kenta Takahashi,
Kenji Aoshima,
Megumi Matsuo,
Yasuharu Ueno,
Yoichi Furukawa,
Kiyoshi Yamaguchi,
Masayuki Ohtsuka,
Soichiro Morinaga,
Yohei Miyagi,
Tomoyuki Yamaguchi,
Naoki Tanimizu,
Hideki Taniguchi
Affiliations
Kenta Takeuchi
Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Shunsuke Tabe
Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
Kenta Takahashi
Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Graduate School of Frontier Sciences, Computational Biology and Medical Science, Kashiwa, Chiba, Japan
Kenji Aoshima
Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Graduate School of Frontier Sciences, Computational Biology and Medical Science, Kashiwa, Chiba, Japan
Megumi Matsuo
Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan; Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
Yasuharu Ueno
Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Yoichi Furukawa
Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Kiyoshi Yamaguchi
Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Masayuki Ohtsuka
Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
Soichiro Morinaga
Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan
Yohei Miyagi
Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Kangawa, Japan
Tomoyuki Yamaguchi
School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
Naoki Tanimizu
Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Corresponding author
Hideki Taniguchi
Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan; Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Corresponding author
Summary: 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.
