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@ARTICLE{Lian:293861,
      author       = {G. Lian and E. Malagola and C. Wei and Q. Shi and J. Zhao
                      and M. Hata and H. Kobayashi and Y. Ochiai and B. Zheng and
                      X. Zhi and F. Wu and R. Tu and O. C. Nápoles and W. Su and
                      L. Li and C. Jing and M. Chen and L. Zamechek and R.
                      Friedman and K. Nowicki-Osuch$^*$ and M. Quante and J. Que
                      and T. C. Wang},
      title        = {p53 mutation biases squamocolumnar junction progenitor
                      cells towards dysplasia rather than metaplasia in
                      {B}arrett's oesophagus.},
      journal      = {Gut},
      volume       = {74},
      number       = {2},
      issn         = {0017-5749},
      address      = {London},
      publisher    = {BMJ Publishing Group},
      reportid     = {DKFZ-2024-01991},
      pages        = {182-196},
      year         = {2025},
      note         = {2025 Jan 17;74(2):182-196},
      abstract     = {While p53 mutations occur early in Barrett's oesophagus
                      (BE) progression to oesophageal adenocarcinoma (EAC), their
                      role in gastric cardia stem cells remains unclear.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.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.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.p53 mutation contributes to BE progression by
                      increasing expansion and fitness of undifferentiated cardia
                      progenitors and preventing their differentiation towards
                      metaplasia.},
      keywords     = {BARRETT'S METAPLASIA (Other) / BARRETT'S OESOPHAGUS (Other)
                      / DYSPLASIA (Other) / OESOPHAGEAL CANCER (Other) / STEM
                      CELLS (Other)},
      cin          = {C150},
      ddc          = {610},
      cid          = {I:(DE-He78)C150-20160331},
      pnm          = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
      pid          = {G:(DE-HGF)POF4-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39353725},
      doi          = {10.1136/gutjnl-2024-332095},
      url          = {https://inrepo02.dkfz.de/record/293861},
}