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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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Cites
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Love, M. I., Huber, W., & Anders, S. (2014) · Genome Biology · doi:10.1186/s13059-014-0550-8 · Cited by 95,106 · cited 2×
“Normalised counts were created using DESeq2 [69] and RPKMs using edgeR's 1213 function [edgeR].”
Fast gapped-read alignment with Bowtie 2
Langmead, B., & Salzberg, S. L. (2012) · Nature Methods · doi:10.1038/nmeth.1923 · Cited by 56,400 · cited 1×
“6) [73] and the output was 1245 preprocessed for variant calling by marking duplicates with Picard (v1.”
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., Garimella, K., Altshuler, D., Gabriel, S., Daly, M., et al. (2010) · Genome Research · doi:10.1101/gr.107524.110 · Cited by 27,895
featureCounts: an efficient general purpose program for assigning sequence reads to genomic features
Liao, Y., Smyth, G. K., & Shi, W. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btt656 · Cited by 27,219
Cingolani, P., Platts, A., Wang, L. L., Coon, M., Nguyen, T., Wang, L., Land, S. J., Lu, X., & Ruden, D. M. (2012) · Fly · doi:10.4161/fly.19695 · Cited by 11,816
TopHat: discovering splice junctions with RNA-Seq
Trapnell, C., Pachter, L. S., & Salzberg, S. L. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp120 · Cited by 11,682
Analysis of protein-coding genetic variation in 60,706 humans
Exome Aggregation Consortium, Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O’Donnell-Luria, A. H., Ware, J. S., Hill, A. J., et al. (2016) · Nature · doi:10.1038/nature19057 · Cited by 9,587
UniProt: the Universal Protein knowledgebase
Apweiler, R. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkh131 · Cited by 7,593
dbSNP: the NCBI database of genetic variation
Sherry, S. T. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.1.308 · Cited by 7,502
UniProt: the universal protein knowledgebase
The UniProt Consortium (2017) · Nucleic Acids Research · doi:10.1093/nar/gkw1099 · Cited by 4,436
TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data
Colaprico, A., Silva, T. C., Olsen, C., Garofano, L., Cava, C., Garolini, D., Sabedot, T. S., Malta, T. M., Pagnotta, S. M., Castiglioni, I., et al. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv1507 · Cited by 4,205 · cited 1×
“10) [79] and by splitting, per gene, the tumour samples into high- and low-expression 1284 groups.”
Sato, T., Stange, D. E., Ferrante, M., Vries, R. G. J., van Es, J. H., van den Brink, S., van Houdt, W. J., Pronk, A., van Gorp, J., Siersema, P. D., et al. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.07.050 · Cited by 3,753 · cited 1×
“Accordingly, 77 mouse and human cancer organoids have recently been established for colon [16-18], 78”
Organoid Models and Applications in Biomedical Research
Xinaris, C., Brizi, V., & Remuzzi, G. (2015) · The Nephron journals/Nephron journals · doi:10.1159/000433566 · Cited by 3,519
Primary liver cancer: Worldwide incidence and trends
Bosch, F. X., Ribes, J., Díaz, M., & Clèries, R. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.09.011 · Cited by 2,473 · cited 1×
“It is the second most 46 common malignancy worldwide in terms of mortality, and incidence rates are rising, mainly 47 due to an increase in associated risk factors such as diabetes and obesity [2, 3].”
SIFT web server: predicting effects of amino acid substitutions on proteins
Sim, N.-L., Kumar, P. N., Hu, J., Henikoff, S., Schneider, G., & Ng, P. C. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks539 · Cited by 2,419
Prospective Derivation of a Living Organoid Biobank of Colorectal Cancer Patients
van de Wetering, M., Francies, H. E., Francis, J. M., Bounova, G., Iorio, F., Pronk, A., van Houdt, W., van Gorp, J., Taylor-Weiner, A., Kester, L., et al. (2015) · Cell · doi:10.1016/j.cell.2015.03.053 · Cited by 2,408
Self-citationCOSMIC: exploring the world's knowledge of somatic mutations in human cancer
Forbes, S. A., Beare, D. M., Gunasekaran, P., Leung, K., Bindal, N., Boutselakis, H., Ding, M., Bamford, S., Cole, C. G., Ward, S. A., et al. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku1075 · Cited by 2,294 · cited 1×
“A cancer related set of variants was defined by adding the following filtering 1261 steps: (v) SNVs which were included in dbSNP (v150) [77] were excluded, with the 1262 exception of those which were also included in COSMIC (v76) [78].”
Organoid models of human and mouse ductal pancreatic cancer
Boj, S. F., Hwang, C.-I., Baker, L. A., Chio, I. I. C., Engle, D. D., Corbo, V., Jager, M., Ponz-Sarvise, M., Tiriac, H., Spector, M. S., et al. (2015) · Cell · doi:10.1016/j.cell.2014.12.021 · Cited by 2,150 · cited 1×
“Accordingly, mouse and human cancer organoids have recently been established for colon16–19, pancreas17,20 and prostate21 tumours, but not, thus far, from liver tumours.”
Self-citationStandards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer
Li, M. M., Datto, M., Duncavage, E. J., Kulkarni, S., Lindeman, N. I., Roy, S., Tsimberidou, A. M., Vnencak‐Jones, C. L., Wolff, D. J., Younes, A., et al. (2016) · Journal of Molecular Diagnostics · doi:10.1016/j.jmoldx.2016.10.002 · Cited by 2,113
A Landscape of Pharmacogenomic Interactions in Cancer
Iorio, F., Knijnenburg, T. A., Vis, D. J., Bignell, G. R., Menden, M. P., Schubert, M., Aben, N., Gonçalves, E., Barthorpe, S., Lightfoot, H., et al. (2016) · Cell · doi:10.1016/j.cell.2016.06.017 · Cited by 2,090 · cited 1×
“This is vastly different to 520 existing 2D cell lines, which albeit they cover the major driver mutations observed in many 521 cancer sub-types [62], no longer present the patient-specific signature and genetic landscape 522”
Self-citationdendextend: an R package for visualizing, adjusting and comparing trees of hierarchical clustering
Galili, T. (2015) · Bioinformatics · doi:10.1093/bioinformatics/btv428 · Cited by 1,826
Schulze, K., Imbeaud, S., Letouzé, E., Alexandrov, L. B., Calderaro, J., Rebouissou, S., Couchy, G., Meiller, C., Shinde, J., Soysouvanh, F., et al. (2015) · Nature Genetics · doi:10.1038/ng.3252 · Cited by 1,803 · cited 1×
“4g), in agreement with previous studies in primary liver cancer [58].”
Patient-Derived Xenograft Models: An Emerging Platform for Translational Cancer Research
Hidalgo, M. M., Amant, F. C., Biankin, A. V., Budínská, E., Byrne, A. T., Caldas, C., Clarke, R. B., de Jong, S., Jonkers, J., Mælandsmo, G. M., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0001 · Cited by 1,797
Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver
Huch, M., Gehart, H., van Boxtel, R., Hamer, K., Blokzijl, F., Verstegen, M. M. A., Ellis, E., van Wenum, M., Fuchs, S. A., de Ligt, J., et al. (2015) · Cell · doi:10.1016/j.cell.2014.11.050 · Cited by 1,619
Self-citationOrganoid Cultures Derived from Patients with Advanced Prostate Cancer
Gao, D., Vela, I., Sboner, A., Iaquinta, P. J., Karthaus, W. R., Gopalan, A., Dowling, C., Wanjala, J. N., Undvall, E. A., Arora, V. K., et al. (2014) · Cell · doi:10.1016/j.cell.2014.08.016 · Cited by 1,559
In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration
Huch, M., Dorrell, C., Boj, S. F., van Es, J. H., Li, V. S. W., van de Wetering, M., Sato, T., Hamer, K., Sasaki, N., Finegold, M. J., et al. (2013) · Nature · doi:10.1038/nature11826 · Cited by 1,555
Self-citationGuidelines for the diagnosis and management of intrahepatic cholangiocarcinoma
Bridgewater, J. A., Galle, P. R., Khan, S. A., Llovet, J. M., Park, J., Patel, T. C., Pawlik, T. M., & Gores, G. J. (2014) · Journal of Hepatology · doi:10.1016/j.jhep.2014.01.021 · Cited by 1,530
Bañales, J. M., Cardinale, V., Carpino, G., Marzioni, M., Andersen, J. B., Invernizzi, P., Lind, G. E., Folseraas, T., Forbes, S. J., Fouassier, L., et al. (2016) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2016.51 · Cited by 1,397 · cited 12×
“Thus, EpCAM, was highly expressed in all CCs (CC-1-3) and CHCs (CHC-1-2) tumouroids and corresponding patients’ tissues, but absent on HCCs tumouroids and tissues (Fig.”
InfluentialVarScan: variant detection in massively parallel sequencing of individual and pooled samples
Koboldt, D. C., Chen, K., Wylie, T., Larson, D. E., McLellan, M. D., Mardis, E. R., Weinstock, G. M., Wilson, R. K., & Ding, L. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp373 · Cited by 1,365
Tissue-specific mutation accumulation in human adult stem cells during life
Blokzijl, F., de Ligt, J., Jager, M., Sasselli, V., Roerink, S., Sasaki, N., Huch, M., Boymans, S., Kuijk, E., Prins, P., et al. (2016) · Nature · doi:10.1038/nature19768 · Cited by 935 · cited 1×
“This was in stark contrast to healthy liver-derived organoids that stably 322 maintained diploid chromosome numbers in culture, in agreement with our previous 323 observations [23] [49].”
Self-citationInternational Consensus Group for Hepatocellular Neoplasia (2008) · Hepatology · doi:10.1002/hep.22709 · Cited by 862
Broutier, L., Andersson-Rolf, A., Hindley, C. J., Boj, S. F., Clevers, H., Koo, B.-K., & Huch, M. (2016) · Nature Protocols · doi:10.1038/nprot.2016.097 · Cited by 834 · cited 7×
“organoids were processed as described in [22, 23] [24].”
InfluentialSelf-citationUnlimited in vitro expansion of adult bi‐potent pancreas progenitors through the Lgr5/R‐spondin axis
Huch, M., Bonfanti, P., Boj, S. F., Sato, T., Loomans, C. J. M., van de Wetering, M., Sojoodi, M., Li, V. S. W., Schuijers, J., Gracanin, A., et al. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.204 · Cited by 726 · cited 1×
“79 80 Based on our previous work in mouse liver and pancreas organoid cultures [21, 22], we 81”
Self-citationThree-dimensional organotypic culture: experimental models of mammalian biology and disease
Shamir, E. R., & Ewald, A. J. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3873 · Cited by 719
Jiao, Y., Pawlik, T. M., Anders, R. A., Selaru, F. M., Streppel, M. M., Lucas, D. J., Niknafs, N., Guthrie, V. B., Maitra, A., Argani, P., et al. (2013) · Nature Genetics · doi:10.1038/ng.2813 · Cited by 689 · cited 1×
“Notably, we found nonsense mutations (frameshifts or 368 stop-gains) in the chromatin remodelling genes ARID1A (HCC-3 and CC-1), ARID2 (HCC-3) 369 and BAP1 (CHC-1), in agreement with previous reports that have highlighted the importance 370 of these genes in both types of primary liver cancers [56, 57] (Fig.”
Morris, E. J., Jha, S., Restaino, C. R., Dayananth, P., Zhu, H., Cooper, A., Carr, D., Deng, Y., Jin, W., Black, S., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0070 · Cited by 676 · cited 1×
“The reason for this difference is unclear, although ERK 462 inhibitors have demonstrated activity in cells with acquired BRAF and MEK inhibitor463 resistance [61].”
Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents
Sharma, S. V., Haber, D. A., & Settleman, J. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2820 · Cited by 600 · cited 2×
“56 57 The development of effective treatments for liver cancer has been hindered by the shortage of 58 reproducible human models to assess the efficacy of candidate therapeutic agents [8].”
Modeling mouse and human development using organoid cultures
Huch, M., & Koo, B. (2015) · Development · doi:10.1242/dev.118570 · Cited by 578 · cited 3×
“Thus retinal, cerebral, kidney, intestinal and 71 stomach organoids (among others) have already been generated from pluripotent stem cells 72 for the study of human development and disease ex vivo [15].”
InfluentialSelf-citationAndersen, J. B., Spee, B., Blechacz, B. R. A., Avital, I., Komuta, M., Barbour, A. P., Conner, E. A., Gillen, M. C., Roskams, T., Roberts, L. R., et al. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.12.005 · Cited by 564 · cited 1×
“Similarly, in CC tumouroids, 224 S100P, S100A11, S100A6 [37], ALDOA [38], CLIC3 and ANKRD22 [39] all commonly 225 upregulated in CC tissues [40-42] were highly expressed, while hepatocyte (ALB, TTR, 226 APOA1 and APOE) and HCC markers (AFP, GPC3) [34] were not expressed or strongly 227 downregulated (Fig.”
Oncogenic transformation of diverse gastrointestinal tissues in primary organoid culture
Li, X., Nadauld, L. D., Ootani, A., Corney, D. C., Pai, R. K., Gevaert, O., Cantrell, M. A., Rack, P. G., Neal, J. T., Chan, C. W. M., et al. (2014) · Nature Medicine · doi:10.1038/nm.3585 · Cited by 449 · cited 2×
“Accordingly, 77 mouse and human cancer organoids have recently been established for colon [16-18], 78”
Mutational landscape of intrahepatic cholangiocarcinoma
Zou, S., Li, J., Zhou, H., Frech, C., Jiang, X., Chu, J. S.-C., Zhao, X., Li, Y., Li, Q., Wang, H., et al. (2014) · Nature Communications · doi:10.1038/ncomms6696 · Cited by 437 · cited 8×
“Thus, EpCAM, was highly expressed in all CCs (CC-1-3) and CHCs (CHC-1-2) tumouroids and corresponding patients’ tissues, but absent on HCCs tumouroids and tissues (Fig.”
InfluentialInactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma
Li, M., Zhao, H., Zhang, X., Wood, L. D., Anders, R. A., Choti, M. A., Pawlik, T. M., Daniel, H. D. J., Kannangai, R., Offerhaus, G. J. A., et al. (2011) · Nature Genetics · doi:10.1038/ng.903 · Cited by 431 · cited 1×
“Notably, we found nonsense mutations (frameshifts or 368 stop-gains) in the chromatin remodelling genes ARID1A (HCC-3 and CC-1), ARID2 (HCC-3) 369 and BAP1 (CHC-1), in agreement with previous reports that have highlighted the importance 370 of these genes in both types of primary liver cancers [56, 57] (Fig.”
Crespo, M., Vilar, E., Tsai, S.-Y., Chang, K., Amin, S., Srinivasan, T., Zhang, T., Pipalia, N. H., Chen, H. J., Witherspoon, M., et al. (2017) · Nature Medicine · doi:10.1038/nm.4355 · Cited by 399
Mechanisms that link the oncogenic epithelial–mesenchymal transition to suppression of anoikis
Frisch, S. M., Schaller, M. D., & Cieply, B. W. (2013) · Journal of Cell Science · doi:10.1242/jcs.120907 · Cited by 295 · cited 1×
“Also, the cell528 matrix interactions established in 3D could prevent anoikis-apoptosis due to detachment from 529 the matrix[64] of those tumoural cells that have not acquired yet all the mutations to survive 530 in a ECM-free milieu, thus facilitating the maintenance of heterogeneous, non-selected 531 populations wi…”
High-resolution characterization of a hepatocellular carcinoma genome
Totoki, Y., Tatsuno, K., Yamamoto, S., Arai, Y., Hosoda, F., Ishikawa, S., Tsutsumi, S., Sonoda, K., Totsuka, H., Shirakihara, T., et al. (2011) · Nature Genetics · doi:10.1038/ng.804 · Cited by 284 · cited 1×
“Also, the distribution of base substitutions for both tissues and tumouroids revealed an over-representation of the T>C/A>G and C>T/G>A transversion, in agreement with the mutational spectrum described for CCs and HCCs42–43 (Fig.”
Oncofetal Gene SALL4 in Aggressive Hepatocellular Carcinoma
Yong, K. J., Gao, C., Lim, J. S. J., Yan, B., Yang, H., Dimitrov, T., Kawasaki, A., Ong, C. W., Wong, K.-F., Lee, S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1300297 · Cited by 257 · cited 8×
“Thus, EpCAM, was highly expressed in all CCs (CC-1-3) and CHCs (CHC-1-2) tumouroids and corresponding patients’ tissues, but absent on HCCs tumouroids and tissues (Fig.”
InfluentialTumor markers for hepatocellular carcinoma
Zhao, Y., Ju, Q., & Li, G. (2013) · Molecular and Clinical Oncology · doi:10.3892/mco.2013.119 · Cited by 247
Exploration of liver cancer genomes
Shibata, T., & Aburatani, H. (2014) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2014.6 · Cited by 202
Identification of a Cholangiocarcinoma-Like Gene Expression Trait in Hepatocellular Carcinoma
Woo, H. G., Lee, J., Yoon, J., Kim, C. Y., Lee, H., Jang, J. J., Yi, N., Suh, K., Lee, K. U., Park, E. S., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-2823 · Cited by 191 · cited 1×
“187 The gene expression patterns of PLC subtypes (HCC, CC and CHC) have been extensively 188 studied [32] and have proved useful in classifying them [33].”
Moeini, A., Sia, D., Zhang, Z., Campreciós, G., Stueck, A., Dong, H. F., Montal, R., Torrens, L., Martinez-Quetglas, I., Fiel, M. I., et al. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.01.010 · Cited by 181 · cited 1×
“174 Remarkably, SALL4 described for a subset of aggressive HCCs [29, 30] and a subset of CHCs 175 [31] was present only in HCC-3 and CHC-2, both in tumouroids as well as in the 176 corresponding patient’s tissue, but absent in all other tissues and tumouroid lines (Suppl.”
Zhang, F., Chen, X., Zhang, W., Dong, H., Xiang, S., Zhang, W., & Zhang, B.-X. (2007) · Histopathology · doi:10.1111/j.1365-2559.2007.02929.x · Cited by 166 · cited 7×
“Thus, EpCAM, was highly expressed in all CCs (CC-1-3) and CHCs (CHC-1-2) tumouroids and corresponding patients’ tissues, but absent on HCCs tumouroids and tissues (Fig.”
InfluentialKalinich, M., Bhan, I., Kwan, T. T., Miyamoto, D. T., Javaid, S., LiCausi, J. A., Milner, J. D., Hong, X., Goyal, L., Sil, S., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1617032114 · Cited by 158 · cited 1×
“215 216 In agreement with the expression of the original tissues, we found the genes AFP, ALB, 217 APOH, FGG, RBP4, TF, AHSG, FGB, (all involved in HCC progression [34]) and recently 218 described as markers of HCC tumour-circulating cells [35], to be highly upregulated (2Log219 FC>6) in HCC tumouroids (Fig.”
Primary liver cancer: Pattern of metastasis
Lee, Y. M., & Geer, D. A. (1987) · Journal of Surgical Oncology · doi:10.1002/jso.2930360107 · Cited by 145 · cited 1×
“400 Liver cancer has been reported to metastasize primarily to the lung and portal lymph nodes 401 [59].”
Borlak, J. T., Meier, T., Halter, R., Spanel, R., & Spanel‐Borowski, K. (2005) · Oncogene · doi:10.1038/sj.onc.1208196 · Cited by 119 · cited 1×
“6c)46.”
Hsieh, S., Huang, S.-F. K., Yu, M., Yeh, T., Chen, T., Lin, Y., Chang, C., Sung, C., Lee, Y., & Hsu, C. (2010) · Molecular Carcinogenesis · doi:10.1002/mc.20627 · Cited by 116 · cited 1×
“Of note, none of these genes had been 305 previously associated to liver cancer, except for STMN1, that had been associated to poor 306 prognosis in HCC but not in CC [48] (Fig 3f-h).”
Liver carcinogenesis: Rodent models of hepatocarcinoma and cholangiocarcinoma
Minicis, S. D., Kisseleva, T., Francis, H., Svegliati‐Baroni, G., Benedetti, A., Brenner, D. A., Alvaro, D., Alpini, G. D., & Marzioni, M. (2012) · Digestive and Liver Disease · doi:10.1016/j.dld.2012.10.008 · Cited by 110
The `dnet¿ approach promotes emerging research on cancer patient survival
Fang, H., & Gough, J. (2014) · Genome Medicine · doi:10.1186/s13073-014-0064-8 · Cited by 98
Establishment and characterisation of six human biliary tract cancer cell lines
Ku, J.-L., Yoon, K.-A., Kim, I., Kim, W. H., Jang, J.-Y., Suh, K.-S., Kim, S.-W., Park, Y., Hwang, J.-H., Yoon, Y.-B., et al. (2002) · British Journal of Cancer · doi:10.1038/sj.bjc.6600440 · Cited by 88 · cited 1×
“In addition, PLC, especially CCs, have proven difficult to 65 propagate in vitro, with only 2 cell lines reported thus far [12, 13].”
Model of fibrolamellar hepatocellular carcinomas reveals striking enrichment in cancer stem cells
Oikawa, T., Wauthier, E., Dinh, T. A., Selitsky, S. R., Reyna‐Neyra, A., Carpino, G., Levine, R., Cardinale, V., Klimstra, D. S., Gaudio, E., et al. (2015) · Nature Communications · doi:10.1038/ncomms9070 · Cited by 88 · cited 1×
“models or of human tumour-derived cell lines propagated in either 2D-culture or as 61 xenografts in mice [8-10].”
Drug Sensitivity Assays of Human Cancer Organoid Cultures
Francies, H. E., Barthorpe, A. S., McLaren-Douglas, A., Barendt, W. J., & Garnett, M. J. (2016) · Methods in molecular biology · doi:10.1007/7651_2016_10 · Cited by 82 · cited 3×
“32 Organoid viability assays were conducted as previously described [18, 60].”
Self-citationGu, Q., Zhang, B., Sun, H., Xu, Q., Tan, Y., Wang, G., Luo, Q., Xu, W., Yang, S., Li, J., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.3969 · Cited by 80 · cited 1×
“544 In that regard, patient derived xenografts (PDXs) have proven useful models for human 545 cancer, including liver cancer [13, 65], as they also retain tumour histopathology, including 546 tumour-infiltrating lymphocytes and the stromal component, and global gene expression and 547 methylation profiles of the patie…”
Drexler, H. G., Fombonne, S., Matsuo, Y., Hu, Z.-B., Hamaguchi, H., & Uphoff, C. (2000) · Leukemia · doi:10.1038/sj.leu.2401604 · Cited by 71
Multilevel models Improve precision and Speed of IC 50 Estimates
Vis, D. J., Bombardelli, L., Lightfoot, H., Iorio, F., Garnett, M. J., & Wessels, L. F. (2016) · Pharmacogenomics · doi:10.2217/pgs.16.15 · Cited by 71
Self-citationOrganoids from adult liver and pancreas: Stem cell biology and biomedical utility
Hindley, C. J., Cordero-Espinoza, L., & Huch, M. (2016) · Developmental Biology · doi:10.1016/j.ydbio.2016.06.039 · Cited by 67 · cited 1×
“We recently have demonstrated that gastric, pancreatic and hepatic organoid cultures derived from adult tissues self-renew and differentiate in vitro, into the corresponding cell types of the tissue-of–origin14–15.”
Self-citationLee, S. D., Park, S., Han, S., Kim, S. H., Kim, Y.-K., Lee, S.-A., Ko, Y. H., & Hong, E. K. (2014) · Hepatobiliary & pancreatic diseases international · doi:10.1016/s1499-3872(14)60275-7 · Cited by 61 · cited 3×
“2% of all PLCs [4] harbours intermediate characteristics between 52 HCC and CC [5].”
InfluentialCombined hepatocellular cholangiocarcinoma: Controversies to be addressed
Wang, A.-Q. (2016) · World Journal of Gastroenterology · doi:10.3748/wjg.v22.i18.4459 · Cited by 53
Biphenotypic (Hepatobiliary) Primary Liver Carcinomas: The Work in Progress
Brunt, E. M., Paradis, V., Sempoux, C. L., & Theise, N. D. (2015) · Hepatic Oncology · doi:10.2217/hep.15.8 · Cited by 52 · cited 1×
“3a-c and Supplementary Table 1)26.”
Ohguchi, S., Nakatsukasa, H., Higashi, T., Ashida, K., Nouso, K., Ishizaki, M., Hino, N., Kobayashi, Y., Uematsu, S., & Tsuji, T. (1998) · Hepatology · doi:10.1002/hep.510270239 · Cited by 47 · cited 1×
“Likewise, AFP a well-established marker for HCCs and a subset of CHCs27, but not expressed in CCs3,5,28–29, was highly expressed in both HCCs and CHC-2 tumouroids, in agreement with the expression pattern of the original patient’s tissue (Fig.”
Cavalloni, G., Neia, C. P., Varamo, C., Casorzo, L., Dell’Aglio, C., Bernabei, P., Chiorino, G., Aglietta, M., & Leone, F. (2015) · Tumor Biology · doi:10.1007/s13277-015-4215-3 · Cited by 38 · cited 3×
“8% engraftment efficiency as reported by 549 [13]), have a long engraftment period (often several months), they are expensive and time550 consuming, and are not tractable for large-scale drug sensitivity testing [66].”
Liver Cancer Oncogenomics: Opportunities and Dilemmas for Clinical Applications
Marquardt, J. U., & Andersen, J. B. (2015) · Hepatic Oncology · doi:10.2217/hep.14.24 · Cited by 22 · cited 2×
“Albeit both, HCC and CC are easily distinguishable by their histological 53 appearance [3, 5] and genetic and transcriptional landscapes [6], with CHC sharing 54 histological features of both [7], PLC is overall a complex entity, which renders each case of 55 the disease unique and in need of precise and personalized…”
Stem Cell Gene SALL4 in Aggressive Hepatocellular Carcinoma: A Cancer Stem Cell-Specific Target?
Yakaboski, E., Jares, A., & Ma, Y. (2013) · Hepatology · doi:10.1002/hep.26956 · Cited by 18 · cited 8×
“Thus, EpCAM, was highly expressed in all CCs (CC-1-3) and CHCs (CHC-1-2) tumouroids and corresponding patients’ tissues, but absent on HCCs tumouroids and tissues (Fig.”
InfluentialA Novel Predictive Equation for Potential Diagnosis of Cholangiocarcinoma
Kraiklang, R., Pairojkul, C., Khuntikeo, N., Imtawil, K., Wongkham, S., & Wongkham, C. (2014) · PLoS ONE · doi:10.1371/journal.pone.0089337 · Cited by 17 · cited 1×
“Similarly, in CC tumouroids, 224 S100P, S100A11, S100A6 [37], ALDOA [38], CLIC3 and ANKRD22 [39] all commonly 225 upregulated in CC tissues [40-42] were highly expressed, while hepatocyte (ALB, TTR, 226 APOA1 and APOE) and HCC markers (AFP, GPC3) [34] were not expressed or strongly 227 downregulated (Fig.”
KAMLUA, S., Patrakitkomjorn, S., Jearanaikoon, P., Menheniott, T. R., Giraud, A. S., & Limpaiboon, T. (2011) · Oncology Reports · doi:10.3892/or.2011.1583 · Cited by 10
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Human organoids: model systems for human biology and medicine
Kim, J., Koo, B.-K., & Knoblich, J. A. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0259-3 · Cited by 2,187
Self-citationDrost, J., & Clevers, H. (2018) · Nature Reviews Cancer · doi:10.1038/s41568-018-0007-6 · Cited by 1,790
Resolving the fibrotic niche of human liver cirrhosis at single-cell level
Ramachandran, P., Dobie, R., Wilson-Kanamori, J. R., Dora, E. F., Henderson, B. E. P., Luu, N. T., Portman, J. R., Matchett, K. P., Brice, M., Marwick, J. A., et al. (2019) · Nature · doi:10.1038/s41586-019-1631-3 · Cited by 1,784
Self-citationHofer, M., & Lutolf, M. P. (2021) · Nature Reviews Materials · doi:10.1038/s41578-021-00279-y · Cited by 1,184
Jacob, F., Salinas, R. D., Zhang, D. Y., Nguyen, P. T. T., Schnoll, J. G., Wong, S. Z. H., Thokala, R., Sheikh, S., Saxena, D., Prokop, S., et al. (2020) · Cell · doi:10.1016/j.cell.2019.11.036 · Cited by 1,149
“Organoids have since been applied to model various cancers, including pancreatic, prostate, liver, breast, bladder, ovarian, and gastrointestinal cancers (Boj et al., 2015; Broutier et al., 2017; Gao et al., 2014; Kopper et al., 2019; Lee et al., 2018; Sachs et al., 2018; Yan et al., 2018).”
Background
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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