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         headline:Organoid cultures recapitulate esophageal adenocarcinoma heterogeneity providing a model for clonality studies and precision therapeutics
         description: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. Esophageal adenocarcinoma (EAC) has a poor 5-year survival rate and lacks robust preclinical models for use in research. Here, the authors show that newly derived organoids recapitulate the transcriptomic, genetic, and morphological landscape of the primary EAC tumors and provide a platform to test drug sensitivity and study tumor clonality.
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      headline:Organoid cultures recapitulate esophageal adenocarcinoma heterogeneity providing a model for clonality studies and precision therapeutics
      description: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. Esophageal adenocarcinoma (EAC) has a poor 5-year survival rate and lacks robust preclinical models for use in research. Here, the authors show that newly derived organoids recapitulate the transcriptomic, genetic, and morphological landscape of the primary EAC tumors and provide a platform to test drug sensitivity and study tumor clonality.
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         type:PostalAddress
      name:Cancer Research UK Cambridge Institute
      address:
         name:Cancer Research UK Cambridge Institute, Cambridge, UK
         type:PostalAddress
      name:Cancer Research UK Cambridge Institute
      address:
         name:Cancer Research UK Cambridge Institute, Cambridge, UK
         type:PostalAddress
      name:MRC Cancer Unit, University of Cambridge
      address:
         name:MRC Cancer Unit, University of Cambridge, Cambridge, UK
         type:PostalAddress
      name:MRC Cancer Unit, University of Cambridge
      address:
         name:MRC Cancer Unit, University of Cambridge, Cambridge, UK
         type:PostalAddress
      name:Cambridge University Hospitals NHS Trust
      address:
         name:Cambridge University Hospitals NHS Trust, Cambridge, UK
         type:PostalAddress
      name:Big Data Institute, University of Oxford
      address:
         name:Big Data Institute, University of Oxford, Oxford, UK
         type:PostalAddress
      name:Oxford NIHR Biomedical Research Centre
      address:
         name:Oxford NIHR Biomedical Research Centre, Oxford, UK
         type:PostalAddress
      name:MRC Cancer Unit, University of Cambridge
      address:
         name:MRC Cancer Unit, University of Cambridge, Cambridge, UK
         type:PostalAddress
      name:Cambridge University Hospitals NHS Trust
      address:
         name:Cambridge University Hospitals NHS Trust, Cambridge, UK
         type:PostalAddress
      name:Wellcome Sanger Institute, Hinxton
      address:
         name:Wellcome Sanger Institute, Hinxton, Cambridge, UK
         type:PostalAddress
ImageObject:
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Person:
      name:Xiaodun Li
      affiliation:
            name:MRC Cancer Unit, University of Cambridge
            address:
               name:MRC Cancer Unit, University of Cambridge, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Hayley E. Francies
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            name:Wellcome Sanger Institute, Hinxton
            address:
               name:Wellcome Sanger Institute, Hinxton, Cambridge, UK
               type:PostalAddress
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      name:Maria Secrier
      affiliation:
            name:Cancer Research UK Cambridge Institute
            address:
               name:Cancer Research UK Cambridge Institute, Cambridge, UK
               type:PostalAddress
            type:Organization
            name:Oncology IMED, AstraZeneca, Chesterford
            address:
               name:Oncology IMED, AstraZeneca, Chesterford, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Juliane Perner
      affiliation:
            name:Cancer Research UK Cambridge Institute
            address:
               name:Cancer Research UK Cambridge Institute, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Ahmad Miremadi
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            name:Cambridge University Hospitals NHS Trust
            address:
               name:Cambridge University Hospitals NHS Trust, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Núria Galeano-Dalmau
      affiliation:
            name:MRC Cancer Unit, University of Cambridge
            address:
               name:MRC Cancer Unit, University of Cambridge, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:William J. Barendt
      affiliation:
            name:Wellcome Sanger Institute, Hinxton
            address:
               name:Wellcome Sanger Institute, Hinxton, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Laura Letchford
      affiliation:
            name:Wellcome Sanger Institute, Hinxton
            address:
               name:Wellcome Sanger Institute, Hinxton, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Genevieve M. Leyden
      affiliation:
            name:Wellcome Sanger Institute, Hinxton
            address:
               name:Wellcome Sanger Institute, Hinxton, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Emma K. Goffin
      affiliation:
            name:Wellcome Sanger Institute, Hinxton
            address:
               name:Wellcome Sanger Institute, Hinxton, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Andrew Barthorpe
      affiliation:
            name:Wellcome Sanger Institute, Hinxton
            address:
               name:Wellcome Sanger Institute, Hinxton, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Howard Lightfoot
      affiliation:
            name:Wellcome Sanger Institute, Hinxton
            address:
               name:Wellcome Sanger Institute, Hinxton, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Elisabeth Chen
      affiliation:
            name:Wellcome Sanger Institute, Hinxton
            address:
               name:Wellcome Sanger Institute, Hinxton, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:James Gilbert
      affiliation:
            name:Wellcome Sanger Institute, Hinxton
            address:
               name:Wellcome Sanger Institute, Hinxton, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Ayesha Noorani
      affiliation:
            name:MRC Cancer Unit, University of Cambridge
            address:
               name:MRC Cancer Unit, University of Cambridge, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Ginny Devonshire
      url:http://orcid.org/0000-0002-1408-8176
      affiliation:
            name:Cancer Research UK Cambridge Institute
            address:
               name:Cancer Research UK Cambridge Institute, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Lawrence Bower
      affiliation:
            name:Cancer Research UK Cambridge Institute
            address:
               name:Cancer Research UK Cambridge Institute, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Amber Grantham
      affiliation:
            name:MRC Cancer Unit, University of Cambridge
            address:
               name:MRC Cancer Unit, University of Cambridge, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Shona MacRae
      affiliation:
            name:MRC Cancer Unit, University of Cambridge
            address:
               name:MRC Cancer Unit, University of Cambridge, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Nicola Grehan
      affiliation:
            name:Cambridge University Hospitals NHS Trust
            address:
               name:Cambridge University Hospitals NHS Trust, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:David C. Wedge
      url:http://orcid.org/0000-0002-7572-3196
      affiliation:
            name:Big Data Institute, University of Oxford
            address:
               name:Big Data Institute, University of Oxford, Oxford, UK
               type:PostalAddress
            type:Organization
            name:Oxford NIHR Biomedical Research Centre
            address:
               name:Oxford NIHR Biomedical Research Centre, Oxford, UK
               type:PostalAddress
            type:Organization
      name:Rebecca C. Fitzgerald
      affiliation:
            name:MRC Cancer Unit, University of Cambridge
            address:
               name:MRC Cancer Unit, University of Cambridge, Cambridge, UK
               type:PostalAddress
            type:Organization
            name:Cambridge University Hospitals NHS Trust
            address:
               name:Cambridge University Hospitals NHS Trust, Cambridge, UK
               type:PostalAddress
            type:Organization
      email:[email protected]
      name:Mathew J. Garnett
      affiliation:
            name:Wellcome Sanger Institute, Hinxton
            address:
               name:Wellcome Sanger Institute, Hinxton, Cambridge, UK
               type:PostalAddress
            type:Organization
PostalAddress:
      name:MRC Cancer Unit, University of Cambridge, Cambridge, UK
      name:Wellcome Sanger Institute, Hinxton, Cambridge, UK
      name:Cancer Research UK Cambridge Institute, Cambridge, UK
      name:Oncology IMED, AstraZeneca, Chesterford, Cambridge, UK
      name:Cancer Research UK Cambridge Institute, Cambridge, UK
      name:Cambridge University Hospitals NHS Trust, Cambridge, UK
      name:MRC Cancer Unit, University of Cambridge, Cambridge, UK
      name:Wellcome Sanger Institute, Hinxton, Cambridge, UK
      name:Wellcome Sanger Institute, Hinxton, Cambridge, UK
      name:Wellcome Sanger Institute, Hinxton, Cambridge, UK
      name:Wellcome Sanger Institute, Hinxton, Cambridge, UK
      name:Wellcome Sanger Institute, Hinxton, Cambridge, UK
      name:Wellcome Sanger Institute, Hinxton, Cambridge, UK
      name:Wellcome Sanger Institute, Hinxton, Cambridge, UK
      name:Wellcome Sanger Institute, Hinxton, Cambridge, UK
      name:MRC Cancer Unit, University of Cambridge, Cambridge, UK
      name:Cancer Research UK Cambridge Institute, Cambridge, UK
      name:Cancer Research UK Cambridge Institute, Cambridge, UK
      name:MRC Cancer Unit, University of Cambridge, Cambridge, UK
      name:MRC Cancer Unit, University of Cambridge, Cambridge, UK
      name:Cambridge University Hospitals NHS Trust, Cambridge, UK
      name:Big Data Institute, University of Oxford, Oxford, UK
      name:Oxford NIHR Biomedical Research Centre, Oxford, UK
      name:MRC Cancer Unit, University of Cambridge, Cambridge, UK
      name:Cambridge University Hospitals NHS Trust, Cambridge, UK
      name:Wellcome Sanger Institute, Hinxton, Cambridge, UK

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