Human primary liver cancer–derived organoid cultures for disease modeling and drug screening
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Authors
Broutier, Laura
Gianmarco Mastrogiovanni,
Monique M.A. Verstegen,
Hayley E. Francies,
Lena Morrill Gavarró,
Charles R Bradshaw,
George E Allen,
Robert Arnes-Benito,
Olga Sidorova,
Marcia P. Gaspersz,
Nikitas Georgakopoulos,
Bon-Kyoung Koo,
Sabine Dietmann,
Susan E. Davies,
Raaj K. Praseedom,
Ruby Lieshout,
Jan N. M. 10 IJzermans,
Stephen J Wigmore,
Kourosh Saeb-Parsy,
Mathew J. Garnett,
Luc J.W. van der Laan,
Meritxell Huch,
Journal Title
Nature Medicine
ISSN
1078-8956
Publisher
Nature Publishing Group
Volume
23
Pages
1424-1435
Language
English
Type
Article
This Version
AM
Metadata
Show full item recordCitation
Broutier, L., Gianmarco Mastrogiovanni,, Monique M.A. Verstegen,, Hayley E. Francies,, Lena Morrill Gavarró,, Charles R Bradshaw,, George E Allen,, et al. (2017). Human primary liver cancer–derived organoid cultures for disease modeling and drug screening. Nature Medicine, 23 1424-1435. https://doi.org/10.1038/nm.4438
Abstract
Human liver cancer research currently lacks in vitro models that can faithfully recapitulate the pathophysiology of the original tumor. We recently described a novel, near-physiological organoid culture system, wherein primary human healthy liver cells form long-term expanding organoids that retain liver tissue function and genetic stability. Here we extend this culture system to the propagation of primary liver cancer (PLC) organoids from three of the most common PLC subtypes: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and combined HCC/CC (CHC) tumors. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumor, allowing for discrimination between different tumor tissues and subtypes, even after long-term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumorogenic potential, histological features and metastatic properties of PLC-derived organoids are preserved in vivo. PLC-derived organoids are amenable for biomarker identification and drug-screening testing and led to the identification of the ERK inhibitor SCH772984 as a potential therapeutic agent for primary liver cancer. We thus demonstrate the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized-medicine approaches for the disease.
Keywords
cancer models, disease model, self-renewal
Sponsorship
M.H. is a Wellcome Trust Sir Henry Dale Fellow and is jointly funded by the Wellcome Trust and the Royal Society (104151/Z/14/Z). L.B. is supported by an EMBO Postdoctoral Fellowship (EMBO ALTF 794-2014) and Marie-Curie Postdoctoral Fellowship (grant no. 656193_H2020-MSCA-IF-2014). G.M. was supported by a Marie Curie Initial Training Network (Marie Curie ITN WntsApp 608180) and a H2020 LSMF4LIFE grant (ECH2020-668350). This work was funded by an NC3Rs International prize, a Beit Prize, a Cambridge Cancer Center-pump priming award (CRUK-RG83267) and, partially, by a NC3Rs project grant (NC/R001162/1), all of them awarded to M.H. Work at the L.J.W.v.d.L lab was funded by the research program InnoSysTox (project number 114027003), by the Netherlands Organisation for Health Research and Development (ZonMw), and part of the research program financed by the Dutch Digestive Foundation (MLDS-Diagnostics project number D16-26). Work in the M.J.G. lab is funded by the Wellcome Trust (102696), Stand Up To Cancer (SU2C-AACRDT1213) and Cancer Research UK (C44943/A22536).
Funder references
European Commission (656193)
WELLCOME TRUST (104151/Z/14/Z)
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC)
EC FP7 MC ITN (608180)
NC3Rs (NC/R001162/1)
Identifiers
External DOI: https://doi.org/10.1038/nm.4438
This record's URL: https://www.repository.cam.ac.uk/handle/1810/268203
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