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Human primary liver cancer–derived organoid cultures for disease modeling and drug screening

Nature Medicine volume 23, pages 1424–1435 (2017)Cite this article

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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.

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Figure 1: Patient-derived primary liver cancer organoid cultures expand long-term in vitro while maintaining the histological architecture of the tumor subtype from which they were derived.
Figure 2: Immunohistochemistry analyses reveal that the PLC tumoroids retain expression patterns of the distinct subtype of the original tissue from which they were derived, even after long-term expansion in culture.
Figure 3: Tumoroids recapitulate the expression profiles of the specific tissue of origin.
Figure 4: Tumoroids preserve the genetic alterations from the original tumor.
Figure 5: In vivo growth and metastatic potential of PLC tumoroids.
Figure 6: PLC tumoroid lines as a platform for drug screening and validation of actionable therapeutic _targets.

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Acknowledgements

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). We thank C. Pacini (Wellcome Trust–Cancer Research UK Gurdon Institute) for help with the clustering analysis of the HCC and CC TCGA cohorts and the samples used in this study. We also thank C. Olpe and N. Hircq (Wellcome Trust–Cancer Research UK Gurdon Institute) for help in the early phases of the project, C. Hindley (Wellcome Trust–Cancer Research UK Gurdon Institute) for editorial assistance, the Gurdon Institute facilities for help with imaging and animal care, S. Moss, K. Harnish (Wellcome Trust–Cancer Research UK Gurdon Institute), M. Paramor and J. Martinez (Wellcome Trust–Medical Research Council Stem Cell Institute) for assistance with sequencing analysis and A. Jah (Cambridge University Hospitals NHS Trust) and J. de Jonge (Erasmus Rotterdam Center) for facilitating the recruitment of patients. Finally, M.H. would like to thank B. Hogan (University of North Carolina—Chapel Hill) and M. Zernicka-Goetz (University of Cambridge) for helpful discussions and critical comments.

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Author notes

  1. Gianmarco Mastrogiovanni, Monique MA Verstegen and Hayley E Francies: These authors contributed equally to this work.

Authors and Affiliations

  1. The Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge, UK

    Laura Broutier, Gianmarco Mastrogiovanni, Charles R Bradshaw, George E Allen, Robert Arnes-Benito, Olga Sidorova & Meritxell Huch

  2. Wellcome Trust—Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK

    Gianmarco Mastrogiovanni, Lena Morrill Gavarró, Bon-Kyoung Koo, Sabine Dietmann & Meritxell Huch

  3. Department of Surgery, Erasmus MC–University Medical Center, Rotterdam, The Netherlands

    Monique MA Verstegen, Marcia P Gaspersz, Ruby Lieshout, Jan N M IJzermans & Luc JW van der Laan

  4. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK

    Hayley E Francies & Mathew J Garnett

  5. Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK

    Nikitas Georgakopoulos & Kourosh Saeb-Parsy

  6. Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

    Susan E Davies

  7. Department of Hepato Pancreato Biliary Surgery, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

    Raaj K Praseedom

  8. Department of Clinical Surgery, Royal Infirmary of Edinburgh, Edinburgh, UK

    Stephen J Wigmore

  9. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK

    Meritxell Huch

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  1. Laura Broutier
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Contributions

L.B. designed and performed experiments and interpreted results. G.M. performed experiments and interpreted results. R.A.-B. and O.S. performed experiments. L.M.G., C.R.B., G.E.A. and S.D. performed bioinformatic analyses. S.E.D. performed the histopathology diagnosis. M.M.A.V., M.P.G., R.L., J.N.M.I.J., S.J.W, R.K.P., N.G. and K.S.P. provided patient material and interpreted clinical data. K.S.P. performed the kidney-capsule transplants. H.E.F. and M.J.G. performed the drug screening, interpreted the results and wrote the drug screening section of the manuscript. M.H. conceived and designed the project, designed and performed experiments and interpreted results. M.H. and L.B. wrote the manuscript. All authors commented on the manuscript.

Corresponding author

Correspondence to Meritxell Huch.

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Supplementary information

Supplementary Figures & Table

Supplementary Figures 1–8 & Supplementary Table 1 (PDF 45208 kb)

Life Sciences Reporting Summary (PDF 170 kb)

Supplementary Dataset 1

RNAseq data analysis (XLSX 9351 kb)

Supplementary Dataset 2

Tumoroids GSEA data (XLSX 722 kb)

Supplementary Dataset 3

Tissues GSEA data (XLSX 625 kb)

Supplementary Dataset 4

WES analysis (XLSX 332 kb)

Supplementary Dataset 5

Drug screening (XLSX 80 kb)

Supplementary Dataset 6

List of antibodies, kits, and primers used (XLSX 46 kb)

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Broutier, L., Mastrogiovanni, G., Verstegen, M. et al. Human primary liver cancer–derived organoid cultures for disease modeling and drug screening. Nat Med 23, 1424–1435 (2017). https://doi.org/10.1038/nm.4438

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