TY - JOUR
T1 - Human primary liver cancer-derived organoid cultures for disease modeling and drug screening
AU - Broutier, Laura
AU - Mastrogiovanni, Gianmarco
AU - Verstegen, Monique M.A.
AU - Francies, Hayley E.
AU - Gavarró, Lena Morrill
AU - Bradshaw, Charles R.
AU - Allen, George E.
AU - Arnes-Benito, Robert
AU - Sidorova, Olga
AU - Gaspersz, Marcia P.
AU - Georgakopoulos, Nikitas
AU - Koo, Bon Kyoung
AU - Dietmann, Sabine
AU - Davies, Susan E.
AU - Praseedom, Raaj K.
AU - Lieshout, Ruby
AU - IJzermans, Jan N.M.
AU - Wigmore, Stephen J.
AU - Saeb-Parsy, Kourosh
AU - Garnett, Mathew J.
AU - Van Der Laan, Luc J.W.
AU - Huch, Meritxell
N1 - Publisher Copyright:
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85039071691&partnerID=8YFLogxK
U2 - 10.1038/nm.4438
DO - 10.1038/nm.4438
M3 - Article
C2 - 29131160
AN - SCOPUS:85039071691
SN - 1078-8956
VL - 23
SP - 1424
EP - 1435
JO - Nature medicine
JF - Nature medicine
IS - 12
ER -