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Organoid cultures recapitulate esophageal adenocarcinoma heterogeneity providing a model for clonality studies and precision therapeutics

Author

Listed:
  • Xiaodun Li

    (MRC Cancer Unit, University of Cambridge)

  • Hayley E. Francies

    (Wellcome Sanger Institute, Hinxton)

  • Maria Secrier

    (Cancer Research UK Cambridge Institute
    Oncology IMED, AstraZeneca, Chesterford)

  • Juliane Perner

    (Cancer Research UK Cambridge Institute)

  • Ahmad Miremadi

    (Cambridge University Hospitals NHS Trust)

  • Núria Galeano-Dalmau

    (MRC Cancer Unit, University of Cambridge)

  • William J. Barendt

    (Wellcome Sanger Institute, Hinxton)

  • Laura Letchford

    (Wellcome Sanger Institute, Hinxton)

  • Genevieve M. Leyden

    (Wellcome Sanger Institute, Hinxton)

  • Emma K. Goffin

    (Wellcome Sanger Institute, Hinxton)

  • Andrew Barthorpe

    (Wellcome Sanger Institute, Hinxton)

  • Howard Lightfoot

    (Wellcome Sanger Institute, Hinxton)

  • Elisabeth Chen

    (Wellcome Sanger Institute, Hinxton)

  • James Gilbert

    (Wellcome Sanger Institute, Hinxton)

  • Ayesha Noorani

    (MRC Cancer Unit, University of Cambridge)

  • Ginny Devonshire

    (Cancer Research UK Cambridge Institute)

  • Lawrence Bower

    (Cancer Research UK Cambridge Institute)

  • Amber Grantham

    (MRC Cancer Unit, University of Cambridge)

  • Shona MacRae

    (MRC Cancer Unit, University of Cambridge)

  • Nicola Grehan

    (Cambridge University Hospitals NHS Trust)

  • David C. Wedge

    (Big Data Institute, University of Oxford
    Oxford NIHR Biomedical Research Centre)

  • Rebecca C. Fitzgerald

    (MRC Cancer Unit, University of Cambridge
    Cambridge University Hospitals NHS Trust)

  • Mathew J. Garnett

    (Wellcome Sanger Institute, Hinxton)

Abstract

Esophageal adenocarcinoma (EAC) incidence is increasing while 5-year survival rates remain less than 15%. A lack of experimental models has hampered progress. We have generated clinically annotated EAC organoid cultures that recapitulate the morphology, genomic, and transcriptomic landscape of the primary tumor including point mutations, copy number alterations, and mutational signatures. Karyotyping of organoid cultures has confirmed polyclonality reflecting the clonal architecture of the primary tumor. Furthermore, subclones underwent clonal selection associated with driver gene status. Medium throughput drug sensitivity testing demonstrates the potential of targeting receptor tyrosine kinases and downstream mediators. EAC organoid cultures provide a pre-clinical tool for studies of clonal evolution and precision therapeutics.

Suggested Citation

  • Xiaodun Li & Hayley E. Francies & Maria Secrier & Juliane Perner & Ahmad Miremadi & Núria Galeano-Dalmau & William J. Barendt & Laura Letchford & Genevieve M. Leyden & Emma K. Goffin & Andrew Barthorp, 2018. "Organoid cultures recapitulate esophageal adenocarcinoma heterogeneity providing a model for clonality studies and precision therapeutics," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05190-9
    DOI: 10.1038/s41467-018-05190-9
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    Cited by:

    1. Marjan M. Naeini & Felicity Newell & Lauren G. Aoude & Vanessa F. Bonazzi & Kalpana Patel & Guy Lampe & Lambros T. Koufariotis & Vanessa Lakis & Venkateswar Addala & Olga Kondrashova & Rebecca L. John, 2023. "Multi-omic features of oesophageal adenocarcinoma in patients treated with preoperative neoadjuvant therapy," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Alvin Wei Tian Ng & Dylan Peter McClurg & Ben Wesley & Shahriar A. Zamani & Emily Black & Ahmad Miremadi & Olivier Giger & Rogier ten Hoopen & Ginny Devonshire & Aisling M. Redmond & Nicola Grehan & S, 2024. "Disentangling oncogenic amplicons in esophageal adenocarcinoma," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Lana Kostic & Carly Leung & Katzrin Ahmad Murad & Snezhina Kancheva & Stefano Perna & Bernett Lee & Nick Barker, 2024. "Lgr5 marks stem/progenitor cells contributing to epithelial and muscle development in the mouse esophagus," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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