Curated Papers > High-Impact Authoritative "Organoid" Literature

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

Literature Information

DOI	10.1038/nm.4438
PMID	29131160
Journal	Nature medicine
Impact Factor	50.0
JCR Quartile	Q1
Publication Year	2017
Times Cited	718
Keywords	liver cancer organoids, disease modeling, drug screening, hepatocellular carcinoma, cholangiocarcinoma
Literature Type	Journal Article
ISSN	1078-8956
Pages	1424-1435
Issue	23(12)
Authors	Laura Broutier, Gianmarco Mastrogiovanni, Monique Ma 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 IJzermans, Stephen J Wigmore, Kourosh Saeb-Parsy, Mathew J Garnett, Luc Jw van der Laan, Meritxell Huch

TL;DR

This study presents a novel organoid culture system that enables the long-term propagation of primary liver cancer organoids from common subtypes, preserving their histological and genomic characteristics. The findings highlight the potential of these organoid models for advancing liver cancer research, particularly in biomarker identification and drug screening, as exemplified by the discovery of the ERK inhibitor SCH772984 as a promising therapeutic agent.

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liver cancer organoids · disease modeling · drug screening · hepatocellular carcinoma · cholangiocarcinoma

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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Primary Questions Addressed

1. How do primary liver cancer-derived organoids compare to traditional cancer cell lines in terms of drug response and genetic stability?
2. What are the specific advantages of using organoid cultures over other in vitro models for studying hepatocellular carcinoma and cholangiocarcinoma?
3. In what ways can the findings from PLC-derived organoid studies be applied to improve personalized medicine strategies for liver cancer patients?
4. What are the potential limitations or challenges in utilizing organoid cultures for long-term studies in liver cancer research?
5. How might the identification of ERK inhibitors, such as SCH772984, influence future therapeutic strategies for treating primary liver cancer?

Key Findings

Research Background and Objectives

Primary liver cancer (PLC) is a leading cause of cancer-related deaths worldwide, with rising incidence due to factors like diabetes and obesity. Current research faces challenges due to a lack of reliable in vitro models that mimic the complexity of human liver tumors. This study aims to develop and characterize organoid cultures derived from primary liver cancer to better model the disease and facilitate drug screening.

Main Methods/Materials/Experimental Design

The study utilized a novel organoid culture system to propagate PLC-derived organoids from surgical specimens of patients with hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), and combined HCC/CC (CHC). The key steps in the experimental design are summarized below:

1. Sample Collection: Tumor tissues were obtained from patients with no history of viral hepatitis.
2. Tissue Digestion: Specimens were minced and digested to isolate tumor cells, with conditions tailored to minimize healthy tissue contamination.
3. Organoid Derivation: The isolated cells were cultured in a defined medium to form organoids.
4. Expansion and Characterization: Organoids were expanded and characterized for histological features, gene expression, and genomic stability.
5. Drug Screening: Organoids were tested for sensitivity to various anticancer compounds, including the ERK inhibitor SCH772984.
6. Xenograft Studies: Organoids were transplanted into immunocompromised mice to assess in vivo tumorigenicity and metastatic potential.

Key Results and Findings

• Organoid Characteristics: The PLC-derived organoids maintained the histological architecture and gene expression profiles of the original tumors, allowing for differentiation between subtypes even after long-term culture.
• Genomic Stability: Whole-exome sequencing revealed that over 80% of the mutations present in the original tumors were retained in the organoids.
• Drug Sensitivity: Drug screening identified SCH772984 as a promising therapeutic agent, demonstrating significant efficacy in reducing tumor growth in vivo.
• Metastatic Potential: Xenograft studies confirmed that the organoids retained the metastatic characteristics of the original tumors, with lung metastases observed in specific models.

Main Conclusions/Significance/Innovation

The study successfully establishes a robust organoid culture system that accurately models the pathophysiology of primary liver cancer. These organoids serve as a valuable platform for drug testing and biomarker discovery, enabling personalized medicine approaches. The identification of new prognostic markers, such as C19ORF48 and UBE2S, underscores the potential of this model in advancing liver cancer research.

Research Limitations and Future Directions

• Limitations: The study does not include immune components, which limits the exploration of tumor-immune interactions. Additionally, the engraftment rates and variability in drug response across different tumor types may pose challenges for broader applications.
• Future Directions: Further research is needed to validate the therapeutic efficacy of identified drugs across a larger cohort of organoid lines and to explore the incorporation of immune components to better mimic the tumor microenvironment.

Summary Table of Key Findings

Feature	Findings
Organoid Maintenance	Preserved histological and genomic features
Drug Sensitivity	Identified SCH772984 as a potential therapeutic agent
Metastatic Behavior	Retained in vivo tumorigenicity and metastasis
Biomarker Discovery	Identified novel prognostic markers

This organoid system provides a significant advancement in the modeling of liver cancer, offering a promising avenue for future therapeutic strategies and personalized treatment approaches.

References

1. p53 alterations in human leukemia-lymphoma cell lines: in vitroartifact or prerequisite for cell immortalization? - H G Drexler;S Fombonne;Y Matsuo;Z B Hu;H Hamaguchi;C C Uphoff - Leukemia (2000)
2. dbSNP: the NCBI database of genetic variation. - S T Sherry;M H Ward;M Kholodov;J Baker;L Phan;E M Smigielski;K Sirotkin - Nucleic acids research (2001)
3. Establishment and characterisation of six human biliary tract cancer cell lines. - J-L Ku;K-A Yoon;I-J Kim;W-H Kim;J-Y Jang;K-S Suh;S-W Kim;Y-H Park;J-H Hwang;Y-B Yoon;J-G Park - British journal of cancer (2002)
4. Primary liver cancer: worldwide incidence and trends. - F Xavier Bosch;Josepa Ribes;Mireia Díaz;Ramon Cléries - Gastroenterology (2004)
5. Epidermal growth factor-induced hepatocellular carcinoma: gene expression profiles in precursor lesions, early stage and solitary tumours. - Jürgen Borlak;Tatiana Meier;Roman Halter;Reinhard Spanel;Katharina Spanel-Borowski - Oncogene (2005)
6. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. - Aravind Subramanian;Pablo Tamayo;Vamsi K Mootha;Sayan Mukherjee;Benjamin L Ebert;Michael A Gillette;Amanda Paulovich;Scott L Pomeroy;Todd R Golub;Eric S Lander;Jill P Mesirov - Proceedings of the National Academy of Sciences of the United States of America (2005)
7. Combined hepatocellular cholangiocarcinoma originating from hepatic progenitor cells: immunohistochemical and double-fluorescence immunostaining evidence. - F Zhang;X-P Chen;W Zhang;H-H Dong;S Xiang;W-G Zhang;B-X Zhang - Histopathology (2008)
8. Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. - - Hepatology (Baltimore, Md.) (2009)
9. TopHat: discovering splice junctions with RNA-Seq. - Cole Trapnell;Lior Pachter;Steven L Salzberg - Bioinformatics (Oxford, England) (2009)
10. VarScan: variant detection in massively parallel sequencing of individual and pooled samples. - Daniel C Koboldt;Ken Chen;Todd Wylie;David E Larson;Michael D McLellan;Elaine R Mardis;George M Weinstock;Richard K Wilson;Li Ding - Bioinformatics (Oxford, England) (2009)

Literatures Citing This Work

1. Organoids lead the cancer attack. - Amber R Smith;Calvin J Kuo - Nature medicine (2017)
2. Circulating tumor cell-derived organoids: Current challenges and promises in medical research and precision medicine. - Prakash P Praharaj;Sujit K Bhutia;Sunitha Nagrath;Rhonda L Bitting;Gagan Deep - Biochimica et biophysica acta. Reviews on cancer (2018)
3. In the literature: February 2018. - Andrés Cervantes - ESMO open (2018)
4. Expansion of airway basal epithelial cells from primary human non-small cell lung cancer tumors. - Robert E Hynds;Assma Ben Aissa;Kate H C Gowers;Thomas B K Watkins;Leticia Bosshard-Carter;Andrew J Rowan;Selvaraju Veeriah;Gareth A Wilson;Sergio A Quezada;Charles Swanton; ;Sam M Janes - International journal of cancer (2018)
5. Liver and Pancreas: Do Similar Embryonic Development and Tissue Organization Lead to Similar Mechanisms of Tumorigenesis? - Elsa Ghurburrun;Ivan Borbath;Frédéric P Lemaigre;Patrick Jacquemin - Gene expression (2018)
6. Core Concept: Organoids have opened avenues into investigating numerous diseases. But how well do they mimic the real thing? - Helen Shen - Proceedings of the National Academy of Sciences of the United States of America (2018)
7. Tumor Evolution and Drug Response in Patient-Derived Organoid Models of Bladder Cancer. - Suk Hyung Lee;Wenhuo Hu;Justin T Matulay;Mark V Silva;Tomasz B Owczarek;Kwanghee Kim;Chee Wai Chua;LaMont J Barlow;Cyriac Kandoth;Alanna B Williams;Sarah K Bergren;Eugene J Pietzak;Christopher B Anderson;Mitchell C Benson;Jonathan A Coleman;Barry S Taylor;Cory Abate-Shen;James M McKiernan;Hikmat Al-Ahmadie;David B Solit;Michael M Shen - Cell (2018)
8. Animal models of cholangiocarcinoma. - Emilien Loeuillard;Samantha R Fischbach;Gregory J Gores;Sumera I Ilyas - Biochimica et biophysica acta. Molecular basis of disease (2019)
9. A PDX/Organoid Biobank of Advanced Prostate Cancers Captures Genomic and Phenotypic Heterogeneity for Disease Modeling and Therapeutic Screening. - Michael L Beshiri;Caitlin M Tice;Crystal Tran;Holly M Nguyen;Adam G Sowalsky;Supreet Agarwal;Keith H Jansson;Qi Yang;Kerry M McGowen;JuanJuan Yin;Aian Neil Alilin;Fatima H Karzai;William L Dahut;Eva Corey;Kathleen Kelly - Clinical cancer research : an official journal of the American Association for Cancer Research (2018)
10. Clinically relevant inflammatory breast cancer patient-derived xenograft-derived ex vivo model for evaluation of tumor-specific therapies. - Bedrich L Eckhardt;Maria Gagliardi;LaKesla Iles;Kurt Evans;Cristina Ivan;Xiuping Liu;Chang-Gong Liu;Glauco Souza;Arvind Rao;Funda Meric-Bernstam;Naoto T Ueno;Geoffrey A Bartholomeusz - PloS one (2018)

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