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Peer-reviewedCC BY-NC-ND 4.0British Journal of Cancer

Dual-oxygen pancreatic cancer organoids recapitulate basal–classical heterogeneity validated by spatial transcriptomics

  • Koichiro Kumano1
  • Hiromitsu Nakahashi1
  • Osamu Shimomura1
  • Yoshimasa Akashi1
  • Yoshihiro Miyazaki1
  • Yohei Owada1
  • Shinji Hashimoto1
  • Kazuto Kamohara1
  • Shuhei Komatsuzaki1
  • Yukihito Kuroda1,2
  • Jaejeong Kim1
  • Pakavarin Louphrasitthiphol1,3
8 more authors
  • Colin R. Goding3
  • Yoshiaki Abe4
  • Mamiko Sakata-Yanagimoto4
  • Noriaki Sakamoto5
  • Daisuke Matsubara5
  • Ayako Suzuki6
  • Yutaka Suzuki6
  • Tatsuya Oda1
6 affiliations
  1. 1Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Institute of Medicine, University of Tsukuba, Tsukuba, Japan
  2. 2Department of Surgery, Columbia University Vagelos College of Physicians and Surgeons, New York, NY USA
  3. 3Nuffield Department of Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK
  4. 4Department of Hematology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan
  5. 5Department of Pathology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan
  6. 6Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
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Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) comprises heterogeneous classical and basal-like subtypes. Although pancreatic cancer organoids (PCOs) are widely used, normoxic cultures preferentially maintain the classical subtype, limiting their ability to represent intrinsic intratumoral heterogeneity. Because PDAC develops in profoundly hypoxic microenvironments, the influence of oxygen tension on organoid modelling remains unclear.

Methods: We performed spatially resolved single-cell transcriptomics on 12 primary PDAC tumours to map the distributions of classical and basal-like cells. Paired organoids were generated under normoxic (20% O₂; NORM-PCOs) and hypoxic (1% O₂; HYPO-PCOs) conditions, and morphology, subtype scores, proliferation and drug responses were compared.

Results: Spatial profiling revealed gradients of basal-like–classical heterogeneity across tumours, with basal-like cells enriched in hypoxic regions. HYPO-PCOs tended to retain basal-like traits, including solid or multi-layered morphology, and increased proliferation, along with a tendency toward reduced sensitivity to chemotherapeutic agents. In contrast, NORM-PCOs more often exhibited mono-layered morphology and showed higher classical subtype scores.

Conclusions: Hypoxic culture conditions promote the preservation of basal-like subpopulations in PDAC organoids, more accurately reflecting the basal–classical heterogeneity of primary tumours. Hypoxia-induced basal-like features remained stable after oxygen switching, indicating a fixed phenotype that informs organoid modelling and offers insight into PDAC progression.

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Cite

BibTeXRIS
BibTeX
@article{kumano2026dualoxygen,
  title = {{Dual-oxygen pancreatic cancer organoids recapitulate basal–classical heterogeneity validated by spatial transcriptomics}},
  author = {Koichiro Kumano and Hiromitsu Nakahashi and Osamu Shimomura and Yoshimasa Akashi and Yoshihiro Miyazaki and Yohei Owada and Shinji Hashimoto and Kazuto Kamohara and Shuhei Komatsuzaki and Yukihito Kuroda and Jaejeong Kim and Pakavarin Louphrasitthiphol and Colin R. Goding and Yoshiaki Abe and Mamiko Sakata-Yanagimoto and Noriaki Sakamoto and Daisuke Matsubara and Ayako Suzuki and Yutaka Suzuki and Tatsuya Oda},
  journal = {British Journal of Cancer},
  year = {2026},
  month = aug,
  doi = {10.1038/s41416-026-03577-w},
  url = {https://doi.org/10.1038/s41416-026-03577-w},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Dual-oxygen pancreatic cancer organoids recapitulate basal–classical heterogeneity validated by spatial transcriptomics
AU  - Koichiro Kumano
AU  - Hiromitsu Nakahashi
AU  - Osamu Shimomura
AU  - Yoshimasa Akashi
AU  - Yoshihiro Miyazaki
AU  - Yohei Owada
AU  - Shinji Hashimoto
AU  - Kazuto Kamohara
AU  - Shuhei Komatsuzaki
AU  - Yukihito Kuroda
AU  - Jaejeong Kim
AU  - Pakavarin Louphrasitthiphol
AU  - Colin R. Goding
AU  - Yoshiaki Abe
AU  - Mamiko Sakata-Yanagimoto
AU  - Noriaki Sakamoto
AU  - Daisuke Matsubara
AU  - Ayako Suzuki
AU  - Yutaka Suzuki
AU  - Tatsuya Oda
PY  - 2026
DA  - 2026/08/22
JO  - British Journal of Cancer
DO  - 10.1038/s41416-026-03577-w
UR  - https://doi.org/10.1038/s41416-026-03577-w
AB  - Background: Pancreatic ductal adenocarcinoma (PDAC) comprises heterogeneous classical and basal-like subtypes. Although pancreatic cancer organoids (PCOs) are widely used, normoxic cultures preferentially maintain the classical subtype, limiting their ability to represent intrinsic intratumoral heterogeneity. Because PDAC develops in profoundly hypoxic microenvironments, the influence of oxygen tension on organoid modelling remains unclear.  Methods: We performed spatially resolved single-cell transcriptomics on 12 primary PDAC tumours to map the distributions of classical and basal-like cells. Paired organoids were generated under normoxic (20% O₂; NORM-PCOs) and hypoxic (1% O₂; HYPO-PCOs) conditions, and morphology, subtype scores, proliferation and drug responses were compared.  Results: Spatial profiling revealed gradients of basal-like–classical heterogeneity across tumours, with basal-like cells enriched in hypoxic regions. HYPO-PCOs tended to retain basal-like traits, including solid or multi-layered morphology, and increased proliferation, along with a tendency toward reduced sensitivity to chemotherapeutic agents. In contrast, NORM-PCOs more often exhibited mono-layered morphology and showed higher classical subtype scores.  Conclusions: Hypoxic culture conditions promote the preservation of basal-like subpopulations in PDAC organoids, more accurately reflecting the basal–classical heterogeneity of primary tumours. Hypoxia-induced basal-like features remained stable after oxygen switching, indicating a fixed phenotype that informs organoid modelling and offers insight into PDAC progression.
SN  - 0007-0920
SN  - 1532-1827
ER  -