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Human primary liver cancer–derived organoid cultures for disease modeling and drug screening
Open accessAbstract
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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“A greater degree of divergence may be attributed to intra-tumor spatial heterogeneity and sampling bias: tumors can be spatially diverse, and organoids generated from a specific portion may lack the representativeness of distant regions130,131.”
From Organoids (2022) · cites this paper as [131]
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“Furthermore, with recent technological advancements (e.g. organoid models and conditionally reprogrammed cell lines), a new generation of cancer cell models is being derived to allow full representation of the histopathological and molecular diversity of tumours (37–42).”
From Cell Model Passports-a hub for clinical, genetic and functional datasets of preclinical cancer models (2019) · cites this paper as [38]
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BackgroundTargeted therapy for hepatocellular carcinoma: Challenges and opportunities
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“Currently, the liver models used for in vitro studies commonly include bioreactors (perfusion model of an isolated liver system) [7], 2D planar primary rat hepatocytes [8,9], 3D-printed liver tissue [10,11], liver organoids [12,13], and liver-on-a-chip systems [14–16].”
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“The rich growth media and 3D matrix of organoid culture conditions have also proven useful for increasing the efficiency and histologic representation of cultures established from patient epithelial tumors including colorectal (20), liver (21), breast (22), pancreatic (23), and CRPC (17) among others.”
BackgroundEstablishment of Patient-Derived Organoids and Drug Screening for Biliary Tract Carcinoma
Saito, Y., Muramatsu, T., Kanai, Y., Ojima, H., Sukeda, A., Hiraoka, N., Arai, E., Sugiyama, Y., Matsuzaki, J., Uchida, R., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.03.088 · Cited by 233
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Basic principles of biobanking: from biological samples to precision medicine for patients
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Probing the Tumor Suppressor Function of BAP1 in CRISPR-Engineered Human Liver Organoids
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“For instance, PDTOs and tumor are comparable in terms of histology 18 and genetics 19 and display clonal evolution in culture 20 .”
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Human primary liver cancer organoids reveal intratumor and interpatient drug response heterogeneity
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“For example, we found that dasatinib, recently reported as effective in a liver cancer organoid study (17), was effective (survival of less than 15%) in only 3 out of 27 PDO lines.”
BackgroundInfluentialOrgan-on-a-Chip for Cancer and Immune Organs Modeling
Sun, W., Luo, Z., Lee, J., Kim, H., Lee, K., Tebon, P., Feng, Y., Dokmeci, M. R., Sengupta, S., & Khademhosseini, A. (2019) · Advanced Healthcare Materials · doi:10.1002/adhm.201801363 · Cited by 221
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“The challenge here, and most probably in all tumor-related personalized medicine applications, is to reduce or eliminate the growth of nonmalignant cells that, in the current expansion protocol 52,53 , have a proliferative advantage at the expense of tumor cell growth.”
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Microfluidics for Drug Development: From Synthesis to Evaluation
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A Pharmacogenomic Landscape in Human Liver Cancers
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“Compared to generating HCC orgnaoids (Broutier et al., 2017; Nuciforo et al., 2018), LIMORE provided a relatively higher efficiency (50% vs ~20%).”
BackgroundMethodPatient‐Derived Organoids Can Guide Personalized‐Therapies for Patients with Advanced Breast Cancer
Chen, P., Zhang, X., Ding, R., Yang, L., Lyu, X., Zeng, J., Lei, J. H., Wang, L., Bi, J., Shao, N., et al. (2021) · Advanced Science · doi:10.1002/advs.202101176 · Cited by 222
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“Interestingly, STMN1 overexpression, which was previously thought to be associated with poor prognosis in only hepatocellular carcinoma, was proven here to be associated with low survival in cholangiocarcinoma in clinical [28].”
BackgroundDeveloping Organoids from Ovarian Cancer as Experimental and Preclinical Models
Maenhoudt, N., Defraye, C., Boretto, M., Jan, Z., Heremans, R., Boeckx, B., Hermans, F., Arijs, I., Cox, B., Van Nieuwenhuysen, E., et al. (2020) · Stem Cell Reports · doi:10.1016/j.stemcr.2020.03.004 · Cited by 186
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BackgroundOrganoid models of gastrointestinal cancers in basic and translational research
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“, breast cancer (70), liver cancer (71, 72), gastric cancer (73), colorectal cancer (74), prostate cancer (75), and pancreatic cancer (76–78).”
BackgroundSomatic cell-derived organoids as prototypes of human epithelial tissues and diseases
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BackgroundOrganoid cultures for cancer modeling
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BackgroundDrug repurposing screening and mechanism analysis based on human colorectal cancer organoids
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“…organoids provide an ideal preclinical model for cancer research, which faithfully recapitulates the molecular characteristics and the heterogeneities of parental tumor tissues (van de Wetering et al., 2015; Broutier et al., 2017; Sachs et al., 2018; Yan et al., 2018; Kopper et al., 2019).”
Metadata
- Authors
- Broutier, L., Mastrogiovanni, G., Verstegen, M. M., Francies, H. E., Gavarró, L. M., Bradshaw, C. R., Allen, G. E., Arnes-Benito, R., Sidorova, O., Gaspersz, M. P., Georgakopoulos, N., Koo, B.-K., Dietmann, S., Davies, S. E., Praseedom, R. K., Lieshout, R., IJzermans, J. N. M., Wigmore, S. J., Saeb-Parsy, K., Garnett, M. J., van der Laan, L. J., & Huch, M.
- Affiliations
- University of Cambridge (GB)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Erasmus MC (NL)
- Wellcome Sanger Institute (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Edinburgh Royal Infirmary (GB)
- Corresponding author
- Huch, Meritxell
- ORCID
- Broutier, Laura
- Mastrogiovanni, Gianmarco
- Verstegen, Monique MA
- Gavarró, Lena Morrill
- Bradshaw, Charles R
- Allen, George E
- Sidorova, Olga
- Gaspersz, Marcia P
- Georgakopoulos, Nikitas
- Koo, Bon-Kyoung
- Dietmann, Sabine
- Davies, Susan E
- Praseedom, Raaj K
- Lieshout, Ruby
- IJzermans, Jan N M
- Wigmore, Stephen J
- Garnett, Mathew J
- Huch, Meritxell
- Venue
- Nature Medicine
- Published
- 2017-11-13
- Volume
- 23
- Issue
- 12
- Pages
- 1424-1435
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC5722201
- OpenAlex
- W2771057425
- Cited by
- 1,471
- References
- 74
- Citations by year
- 2026: 151 · 2025: 163 · 2024: 203 · 2023: 182 · 2022: 204 · 2021: 243 · 2020: 151 · 2019: 99 · 2018: 73 · 2017: 2
- FWCI
- 39.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- HAL (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo
- Funders
- Wellcome Trust (104151/Z/14/Z, C44943/A22536, 104151, 102696)
- Cancer Research UK (102696, C44943/A22536, 22536)
- University of Cambridge
- European Commission (656193, 608180)
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/R001162/1)
- ZonMw
- Cambridge University Hospitals
- National Centre for the Replacement Refinement and Reduction of Animals in Research (NC/R001162/1)
- Stand Up To Cancer (SU2C-AACRDT1213)
- Horizon 2020 Framework Programme (MSCA-IF-2014)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- primary liver cancer, tumor organoids, hepatocellular carcinoma, cholangiocarcinoma, organoid culture, disease modeling, drug screening, xenografts, metastasis, biomarker discovery, ERK inhibitor, SCH772984, personalized medicine
- MeSH terms
- Animals, Antineoplastic Agents, Bile Duct Neoplasms, Drug Screening Assays, Antitumor, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Organoids, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Mice, SCID, Mice, Inbred NOD, Cholangiocarcinoma, Xenograft Model Antitumor Assays, Cell Proliferation, Mice, Precision Medicine, Transcriptome, Primary Cell Culture
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