Human Pancreatic Tumor Organoids Reveal Loss of Stem Cell Niche Factor Dependence during Disease Progression
Open accessAbstract
Despite recent efforts to dissect the inter-tumor heterogeneity of pancreatic ductal adenocarcinoma (PDAC) by determining prognosis-predictive gene expression signatures for specific subtypes, their functional differences remain elusive. Here, we established a pancreatic tumor organoid library encompassing 39 patient-derived PDACs and identified 3 functional subtypes based on their stem cell niche factor dependencies on Wnt and R-spondin. A Wnt-non-producing subtype required Wnt from cancer-associated fibroblasts, whereas a Wnt-producing subtype autonomously secreted Wnt ligands and an R-spondin-independent subtype grew in the absence of Wnt and R-spondin. Transcriptome analysis of PDAC organoids revealed gene-expression signatures that associated Wnt niche subtypes with GATA6-dependent gene expression subtypes, which were functionally supported by genetic perturbation of GATA6. Furthermore, CRISPR-Cas9-based genome editing of PDAC driver genes (KRAS, CDKN2A, SMAD4, and TP53) demonstrated non-genetic acquisition of Wnt niche independence during pancreas tumorigenesis. Collectively, our results reveal functional heterogeneity of Wnt niche independency in PDAC that is non-genetically formed through tumor progression.
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Tumor cells from liquid samples such as peripheral blood, ascites, and pleural effusions can be used as starting material to generate organoids.
“Tumor cells isolated from liquid samples such as peripheral blood52, ascites50,53, and pleural effusions54 can also be used as starting material to generate organoids.”
From Organoids (2022) · cites this paper as [52]
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- Authors
- Seino, T., Kawasaki, S., Shimokawa, M., Tamagawa, H., Toshimitsu, K., Fujii, M., Ohta, Y., Matano, M., Nanki, K., Kawasaki, K., Takahashi, S., Sugimoto, S., Iwasaki, E., Takagi, J., Itoi, T., Kitago, M., Kitagawa, Y., Kanai, T., & Sato, T.
- Affiliations
- Keio University (JP)
- Institute for Protein Research, The University of Osaka (JP)
- Tokyo Medical University (JP)
- Corresponding author
- Sato, Toshiro
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 22
- Issue
- 3
- Pages
- 454-467.e6
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W2783122422
- Cited by
- 631
- References
- 51
- Citations by year
- 2026: 57 · 2025: 80 · 2024: 71 · 2023: 73 · 2022: 81 · 2021: 114 · 2020: 76 · 2019: 57 · 2018: 22
- FWCI
- 25.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Agency for Medical Research and Development
- Keio University
- Stanford University
- Ministry of Education, Culture, Sports, Science and Technology
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- pancreatic ductal adenocarcinoma, tumor organoids, Wnt signaling, R-spondin, stem cell niche, cancer-associated fibroblasts, GATA6, tumor heterogeneity, KRAS, CDKN2A, SMAD4, TP53
- MeSH terms
- Epithelial Cells, Fibroblasts, Genetic Engineering, Humans, Ligands, Organoids, Pancreatic Neoplasms, Gene Expression Regulation, Neoplastic, Disease Progression, GATA6 Transcription Factor, Stem Cell Niche, Wnt Signaling Pathway, CRISPR-Cas Systems
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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