The treatment of pancreatic cancer, an aggressive form of cancer associated with high mortality rates, is challenging owing to limited options and anticancer screening models. High mortality has been attributed to the unique tumor microenvironment (TME). Researchers from Japan have created a pancreatic ductal adenocarcinoma (PDAC) organoid model using human-induced pluripotent stem cell (hiPSC) technology, simulating desirable TME properties. Their research findings have far-reaching consequences in the field of cancer biology.
Pancreatic ductal adenocarcinoma (PDAC), that arises from pancreatic epithelial cells, is the most common form of pancreatic cancer, with a very high mortality rate. This elevated mortality is associated with the unique tumor microenvironment (TME), known for increased resistance to chemotherapy and high metastatic potential. TME is characterized by the presence of a complex stromal structure comprising cancer-associated fibroblasts (CAFs), tumor endothelial cells (TECs), and a variety of immune cells.
CAFs are specific cells, primarily involved in the overall aggressiveness and spread of cancer cells. These cells can further be categorized into several types based on their cellular characteristics and roles, such as inflammatory, myo-fibroblastic, and antigen-presenting CAFs. Therefore, the development of a cell culture system for PDAC that mimics the unique TME involving different types of CAFs, is the need of the hour.
To this end, a research team from Japan attempted to create cancer cell organoid systems that can effectively resemble PDAC and act as a screening tool in anticancer research. Dr. Takeuchi Kenta, a research assistant at the Institute of Medical Science, including Associate Professor Tanimizu Naoki, and Professor Taniguchi Hideki, both from the Institute of Medical Science, The University of Tokyo, were involved in this novel research. Their research findings were published in volume 42, issue 11 of the Cell Reports journal on November 28, 2023.
Dr. Takeuchi Kenta briefly discusses his motivation behind the research. He says, “To reproduce the complexity of PDAC-TME in cell culture models is challenging. Therefore, we used human-induced pluripotent stem cell (hiPSC)-derived mesenchymal cells that can differentiate to multiple types of CAFs and established a novel PDAC organoid.”
The research team used patient-derived PDAC cells with hiPSC-derived endothelial and mesenchymal cells to create fused pancreatic cancer organoid (FPCO). This innovative approach yielded two distinct FPCOs, a proliferative FPCO (pFPCO), and a quiescent FPCO (qFPCO), which resemble a typical patient’s PDAC tissue. Notably, qFPCOs exhibited strong chemo-resistance capabilities, whereas pFPCOs could reproliferate after initial drug treatment. Using advanced techniques such as stem cell technology along with analyses like single cell RNA sequencing, and in-vitro cancer assays, the functional properties of the PDAC organoid system were studied and characterized.
Dr. Tanimizu Naoki concludes, “PDAC is a disease that often requires surgical resection and has no other viable treatment options. Also, anti-PDAC drugs have generally failed at different stages of clinical trials. Hence, PDAC organoids with unique TME profiles should be used for anticancer drug screening. Our PDAC model can help future research in cancer biology and in personalized healthcare.”
Thanks to the research team for the creation of a novel PDAC organoid system that can alter the landscape of cancer biology as an effective screening tool!
Creation of Novel Pancreatic Cancer Models as Drug Screening Tools
Researchers from Japan have created a pancreatic ductal adenocarcinoma (PDAC) organoid model using human-induced pluripotent stem cell (hiPSC) technology, simulating desirable properties of the tumor microenvironment (TME).
Reference
Journal：
Cell Reports
Title of original paper：Incorporation of human iPSC-derived stromal cells creates a pancreatic cancer organoid with heterogeneous cancer-associated fibroblasts
Cell Reports
Title of original paper：Incorporation of human iPSC-derived stromal cells creates a pancreatic cancer organoid with heterogeneous cancer-associated fibroblasts
DOI：
10.1016/j.celrep.2023.113420
Authors：
Kenta Takeuchi1, Shunsuke Tabe1,2, Kenta Takahashi1,3, Kenji Aoshima1,3, Megumi Matsuo2,4, Yasuharu Ueno1, Yoichi Furukawa5, Kiyoshi Yamaguchi5, Masayuki Ohtsuka2, Soichiro Morinaga6, Yohei Miyagi7, Tomoyuki Yamaguchi8, Naoki Tanimizu1,9,*, and Hideki Taniguchi1,4,5,*
*Corresponding author
Affiliations：
1 Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
2 Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
3 Graduate School of Frontier Sciences, Computational Biology and Medical Science, Kashiwa, Chiba, Japan
4 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 Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan
7 Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Kangawa, Japan
8 School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
9 Lead contact
2 Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
3 Graduate School of Frontier Sciences, Computational Biology and Medical Science, Kashiwa, Chiba, Japan
4 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 Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan
7 Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Kangawa, Japan
8 School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
9 Lead contact
About Research Assistant Takeuchi Kenta
Dr. Takeuchi Kenta is a Research Assistant at Division of Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Japan. His research interests are human-induced pluripotent stem cells (iPSCs), cancer research. He has engaged in in vitro reproduction of PDAC tissue to improve the poor clinical adaptability of anti-PDAC drug development and to reveal the mechanism of PDAC's malignant transformation.About Associate Professor Tanimizu Naoki
Dr. Tanimizu Naoki is an Associate Professor at the Division of Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Japan. His research interests include hepatic stem cells, liver development and regeneration, and epithelial morphogenesis. He has authored numerous original research articles, scientific reviews, and book chapters.UTokyo PEOPLE
Dr. Tanimizu Naoki
About Professor Taniguchi Hideki
Dr. Taniguchi Hideki serves as a Professor at the Division of Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Japan. His major research areas include novel organoid culture technologies, human-induced pluripotent stem cells (iPSCs), cancer research, and regenerative medicine. Over the years, he has published 180 research articles which have been cited more than 8,000 times.UTokyo PEOPLE
Dr. Taniguchi Hideki
Media contact
Affiliation: Project Coordination Office, The Institute of Medical Science, The University of Tokyohttps://www.ims.u-tokyo.ac.jp/