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

doi:10.1016/j.celrep.2023.113420

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

Cell Rep. 2023 Nov 28;42(11):113420. doi: 10.1016/j.celrep.2023.113420. Epub 2023 Nov 12.

Authors

Affiliations

¹ Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
² 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.
³ 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.
⁴ 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.
⁵ Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁶ Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
⁷ Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.
⁸ Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Kangawa, Japan.
⁹ School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
¹⁰ Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Electronic address: tanimizu@g.ecc.u-tokyo.ac.jp.
¹¹ 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. Electronic address: rtanigu@g.ecc.u-tokyo.ac.jp.

PMID: 37955987
DOI: 10.1016/j.celrep.2023.113420

Abstract

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.

Keywords: CP: Cancer; air-liquid interface culture; drug resistance; induced pluripotent stem cell; matrix free; pancreatic ductal adenocarcinoma; re-proliferation; tumor heterogeneity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cancer-Associated Fibroblasts* / metabolism
Carcinoma, Pancreatic Ductal* / pathology
Cell Line, Tumor
Endothelial Cells / metabolism
Humans
Induced Pluripotent Stem Cells* / metabolism
Organoids / metabolism
Pancreatic Neoplasms* / pathology
Stromal Cells / metabolism
Tumor Microenvironment