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  • p53 mutation biases squamocolumnar junction progenitor cells towards dysplasia rather than metaplasia in Barrett’s oesophagus

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Upper GI cancer
Original research
p53 mutation biases squamocolumnar junction progenitor cells towards dysplasia rather than metaplasia in Barrett’s oesophagus
  1. Guodong Lian1,2,3,
  2. Ermanno Malagola1,
  3. Chengguo Wei4,
  4. Qiongyu Shi1,5,
  5. Junfei Zhao6,
  6. Masahiro Hata1,
  7. Hiroki Kobayashi1,
  8. Yosuke Ochiai1,
  9. Biyun Zheng1,
  10. Xiaofei Zhi1,
  11. Feijing Wu1,
  12. Ruhong Tu1,
  13. Osmel Companioni Nápoles1,
  14. Wenjing Su7,
  15. Leping Li2,3,
  16. Changqing Jing2,3,
  17. Man Chen4,8,9,
  18. Leah Zamechek1,
  19. Richard Friedman10,
  20. Karol Nowicki-Osuch11,12,
  21. Michael Quante13,
  22. Jianwen Que14,
  23. Timothy C Wang1,15
  1. 1 Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA
  2. 2 Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
  3. 3 Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
  4. 4 Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  5. 5 Department of Biostatistics, Columbia University Mailman School of Public Health, New York, NY, USA
  6. 6 Department of Systems Biology, Columbia University, New York, NY, USA
  7. 7 Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
  8. 8 Department of Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
  9. 9 Department of Critical Care Medicine, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
  10. 10 Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA
  11. 11 German Cancer Research Center (DKFZ) Heidelberg, Tumorigenesis and Molecular Cancer Prevention Group, Heidelberg, Germany
  12. 12 Herbert and Florence Irving Institute for Cancer Dynamics, Columbia University, New York, NY, USA
  13. 13 Klinik für Innere Medizin II, Universitätsklinikum Freiburg, Munchen, Germany
  14. 14 Columbia Center for Human Development, Columbia University Irving Medical Center, New York, NY, USA
  15. 15 Columbia University Digestive and Disease Research Center, New York, NY, USA
  1. Correspondence to Professor Timothy C Wang; tcw21{at}cumc.columbia.edu

Abstract

Background While p53 mutations occur early in Barrett’s oesophagus (BE) progression to oesophageal adenocarcinoma (EAC), their role in gastric cardia stem cells remains unclear.

Objective This study investigates the impact of p53 mutation on the fate and function of cardia progenitor cells in BE to EAC progression, particularly under the duress of chronic injury.

Design We used a BE mouse model (L2-IL1β) harbouring a Trp53 mutation (R172H) to study the effects of p53 on Cck2r+ cardia progenitor cells. We employed lineage tracing, pathological analysis, organoid cultures, single-cell RNA sequencing (scRNA-seq) and computational analyses to investigate changes in progenitor cell behaviour, differentiation patterns and tumour progression. Additionally, we performed orthotopic transplantation of sorted metaplastic and mutant progenitor cells to assess their tumourigenic potential in vivo.

Results The p53 mutation acts as a switch to expand progenitor cells and inhibit their differentiation towards metaplasia, but only amidst chronic injury. In L2-IL1β mice, p53 mutation increased progenitors expansion and lineage-tracing with a shift from metaplasia to dysplasia. scRNA-seq revealed dysplastic cells arise directly from mutant progenitors rather than progressing through metaplasia. In vitro, p53 mutation enhanced BE progenitors’ organoid-forming efficiency, growth, DNA damage resistance and progression to aneuploidy. Sorted metaplastic cells grew poorly with no progression to dysplasia, while mutant progenitors gave rise to dysplasia in orthotopic transplantation. Computational analyses indicated that p53 mutation inhibited stem cell differentiation through Notch activation.

Conclusions p53 mutation contributes to BE progression by increasing expansion and fitness of undifferentiated cardia progenitors and preventing their differentiation towards metaplasia.

  • DYSPLASIA
  • BARRETT'S OESOPHAGUS
  • STEM CELLS
  • OESOPHAGEAL CANCER
  • BARRETT'S METAPLASIA

Data availability statement

Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information.

https://doi.org/10.1136/gutjnl-2024-332095

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    Data availability statement

    Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information.

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    Footnotes

    • X @LeahZam

    • Contributors Conceptualisation: GL, EM, TCW and MQ; methodology: GL, EM, OCN and TCW; software and formal analysis: JZ, KN-O and RF; investigation: GL, EM, QS, JZ, HK, YO, BZ, RT, XZ, FW, OCN, WS, LL, CJ, CW, MC and LZ; writing–original draft: GL; writing–review and editing: GL, EM, JZ, RF, MQ, JQ and TCW; supervision: TCW. TCW is the guarantor.

    • Funding This research was funded by NCI grants R35CA210088 (TCW), and R01CA272901 (TCW, JQ) and a Department of Defense grant W81XWH-21-10901 (TCW). Furthermore, this study received support in part from NIH grants R01DK120650 (JQ) and R01DK132251 (JQ and CL). RF is supported by NIH grants 5R01DK128195 and 5P30CA013696 (Cancer Center Support Grant). KN-O received support from NIH R01 CA272891-01. This work was also supported by the NIH/NCI Cancer Center Support Grant (P30CA013696) and used the resources of the Herbert Irving Comprehensive Cancer Center, including the Flow Cytometry Shared Resources, Molecular Pathology/MPSR, Genomics and High Throughput Screening, and the Genetically Modified Mouse Model Shared Resource (GMMMSR); as well as the Columbia University Digestive and Liver Disease Research Center (CU-DLDRC) grant 1P30DK132710 and its Bio-Imaging, Organoid, Biospecimen and Bioinformatics cores. Additionally, this study received support from Shandong NSF grants: ZR2020MH205 and WSR2023006.

    • Competing interests None declared.

    • 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.