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GI cancer
Original research
Divergent lineage trajectories and genetic landscapes in human gastric intestinal metaplasia organoids associated with early neoplastic progression
  1. Sarah S K Yue1,2,
  2. Yin Tong1,2,
  3. Hoi Cheong Siu1,2,
  4. Siu Lun Ho1,
  5. Simon Y K Law3,
  6. Wai Yin Tsui1,2,
  7. Dessy Chan1,2,
  8. Yuanhua Huang4,5,
  9. Annie S Y Chan1,
  10. Shui Wa Yun1,
  11. Ho Sang Hui1,
  12. Jee-Eun Choi1,
  13. Matthew S S Hsu1,
  14. Frank P L Lai1,2,
  15. April S Chan1,2,
  16. Siu Tsan Yuen1,6,
  17. Hans Clevers7,
  18. Suet Yi Leung1,2,8,9,
  19. Helen H N Yan1,2
  1. 1 Department of Pathology, School of Clinical Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
  2. 2 Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China
  3. 3 Department of Surgery, School of Clinical Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
  4. 4 School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
  5. 5 Department of Statistics and Actuarial Science, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
  6. 6 Department of Pathology, St. Paul’s Hospital, No. 2, Eastern Hospital Road, Causeway Bay, Hong Kong SAR, China
  7. 7 Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Uppsalalaan 8, Oncode Institute, Utrecht, The Netherlands
  8. 8 The Jockey Club Centre for Clinical Innovation and Discovery, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
  9. 9 Centre for PanorOmic Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
  1. Correspondence to Dr Suet Yi Leung; suetyi{at}hku.hk; Dr Helen H N Yan; yanhelen{at}hku.hk

Abstract

Background Gastric intestinal metaplasia (IM) is a precancerous stage spanning a morphological spectrum that is poorly represented by human cell line models.

Objective We aim to establish and characterise human IM cell models to better understand IM progression along the cancer spectrum.

Design A large human gastric IM organoid (IMO) cohort (n=28), their clonal derivatives and normal gastric organoids (n=42) for comparison were established. Comprehensive multi-omics profiling and functional characterisation were performed.

Results Single-cell transcriptomes revealed IMO cells spanning a spectrum from hybrid gastric/intestinal to advanced intestinal differentiation. Their lineage trajectories connected different cycling and quiescent stem and progenitors, highlighting differences in gastric to IM transition and the potential origin of IM from STMN1 cycling isthmus stem cells. Hybrid IMOs showed impaired differentiation potential, high lineage plasticity beyond gastric or intestinal fates and reactivation of a fetal gene programme.

Cell populations in gastric IM and cancer tissues were highly similar to those derived from IMOs and exhibited a fetal signature. Genomically, IMOs showed elevated mutation burden, frequent chromosome 20 gain and epigenetic deregulation of many intestinal and gastric genes. Functionally, IMOs were FGF10 independent and showed downregulated FGFR2. Several IMOs exhibited a cell-matrix adhesion independent subpopulation that displayed chromosome 20 gain but lacked key cancer driver mutations, potentially representing the earliest neoplastic precursor of IM-induced gastric cancer.

Conclusions Overall, our IMO biobank captured the heterogeneous nature of IM, revealing mechanistic insights on IM pathogenesis and progression, offering an ideal platform for studying early gastric neoplastic transformation and chemoprevention.

  • gastric cancer
  • gastric intestinal metaplasia
  • organoid model

Data availability statement

Data are available in a public, open access repository. The WES, RNAseq, scRNAseq and scCNV data were deposited into the European Genome-Phenome Archive (EGAS00001007899). RNAseq, scRNAseq and methylation data were deposited to GEO, GSE210995.

https://doi.org/10.1136/gutjnl-2024-332594

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    Data availability statement

    Data are available in a public, open access repository. The WES, RNAseq, scRNAseq and scCNV data were deposited into the European Genome-Phenome Archive (EGAS00001007899). RNAseq, scRNAseq and methylation data were deposited to GEO, GSE210995.

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    Footnotes

    • SYL and HHNY are joint senior authors.

    • SSKY and YT contributed equally.

    • Contributors SYL and HHNY are the guarantors of this study. HHNY and SYL conceived, designed and supervised the study. SSKY, SLH, WYT, DC, ASYC, SWY, HSH, J-EC, MSSH, FPLL, STY, SYL and HHNY collected data, performed experiments and/or analysed data. YT and HCS performed the bioinformatics data analysis. SYKL contributed clinical data and samples. YH provided advice on bioinformatic analysis of scRNAseq data. HC contributed protocols and/or reagents and critical comments on the manuscript. SYL, HHNY, SSKY and YT wrote the manuscript with assistance from ASC. All authors contributed to the manuscript through comments and approved the final version.

    • Funding This work was supported by a theme-based research grant (project no. T12-710/16-R) from the Research Grants Council of the Hong Kong SAR, China; the Centre for Oncology and Immunology under the Health@InnoHK Initiative funded by the Innovation and Technology Commission, The Government of Hong Kong SAR, China; a donation from the Hong Kong Jockey Club and the Kadoorie Charitable Foundation. Functional characterisation of organoids were partially supported by the General Research Fund (project no. 17108616) and scRNA-seq of intestinal organoid by General Research Fund (project no. 17107219) from the Research Grants Council of the Hong Kong SAR, China. SSKY is supported by a Start-up Fund, The University of Hong Kong. J-EC is a recipient of the RGC postdoctoral fellowship in Hong Kong SAR (PDFS2223-7S04).

    • Competing interests SYL and STY have received research sponsorships from Pfizer, Merck, Servier. HC is an inventor on multiple patents related to organoid technology and one patent on a Matrigel replacement. He is also currently head of Roche’s R&D in Basel, as a member of the executive board. His full disclosures can be found on the following website: www.uu.nl/staff/JCClevers/Additional functions. The other authors declare no competing interests.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.