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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Li, Xiaodun 
Francies, Hayley 
Secrier, Maria 
Pener, Juliane 
Miremadi, Ahmad 

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 has confirmed polyclonality reflecting the clonal architecture of the primary and 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.

Description

Keywords

Adenocarcinoma, Aged, Aged, 80 and over, Clonal Evolution, DNA Copy Number Variations, DNA Mutational Analysis, Drug Screening Assays, Antitumor, Esophageal Neoplasms, Female, Humans, Inhibitory Concentration 50, Karyotyping, Male, Middle Aged, Mutation, Organoids, Precision Medicine, Receptor Protein-Tyrosine Kinases, Sequence Analysis, RNA, Transcriptome

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

9

Publisher

Springer Nature
Sponsorship
Cancer Research UK (22131)
NIHR Clinical Research Network Eastern (via Cambridge University Hospitals NHS Foundation Trust (CUH)) (876523)
Medical Research Council (MC_UU_12022/2)