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

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 Barthorpe, Howard Lightfoot, Elisabeth Chen, James Gilbert, Ayesha Noorani, Ginny Devonshire, Lawrence Bower, Amber Grantham, Shona MacRae, Nicola Grehan, David C. Wedge, Rebecca C. Fitzgerald () and Mathew J. Garnett
Additional contact information
Xiaodun Li: MRC Cancer Unit, University of Cambridge
Hayley E. Francies: Wellcome Sanger Institute, Hinxton
Maria Secrier: Cancer Research UK Cambridge Institute
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
Rebecca C. Fitzgerald: MRC Cancer Unit, University of Cambridge
Mathew J. Garnett: Wellcome Sanger Institute, Hinxton

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05190-9

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