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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Greater genomic divergence between tumor organoids and the parent tumor may be due to intra-tumor spatial heterogeneity and sampling bias, because organoids from one portion may not represent distant regions.
“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]
The Results section, “Liver tumouroids retain the genetic alterations present in the original tumour tissue” (page unavailable), reports that some variants in the parent tissue were not retained in the corresponding organoids. Neither that section nor the Discussion attributes the difference to spatial heterogeneity or sampling bias, or assesses whether organoids from one portion represent distant tumour regions. (LLM, conf=0.82)
Experimental — accuracy not yet measuredRecent technological advancements (e.g. organoid models and conditionally reprogrammed cell lines) have led to a new generation of cancer cell models being derived to allow full representation of the histopathological and molecular diversity of tumours.
“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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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× · see citing works
“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 · see citing works
Multilevel models Improve precision and Speed of IC <sub>50</sub> 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 · see citing works
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 65 · cited 1× · see citing works
“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× · see citing works
“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 · see citing works
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× · see citing works
“3a-c and Supplementary Table 1)26.”
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“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× · see citing works
“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× · see citing works
“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 17 · cited 8× · see citing works
“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× · see citing works
“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.”
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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 · see citing works
Self-citationDrost, J., & Clevers, H. (2018) · Nature Reviews Cancer · doi:10.1038/s41568-018-0007-6 · Cited by 1,790 · see citing works
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 · see citing works
Self-citationHofer, M., & Lutolf, M. P. (2021) · Nature Reviews Materials · doi:10.1038/s41578-021-00279-y · Cited by 1,184 · see citing works
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 · see citing works
“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).”
BackgroundAdvances in organ-on-a-chip engineering
Zhang, B., Korolj, A., Lai, B. F. L., & Radisic, M. (2018) · Nature Reviews Materials · doi:10.1038/s41578-018-0034-7 · Cited by 1,017 · see citing works
Zhao, Z., Chen, X., Dowbaj, A. M., Sljukic, A., Bratlie, K., Lin, L., Fong, E. L. S., Balachander, G. M., Chen, Z., Soragni, A., et al. (2022) · Nature Reviews Methods Primers · doi:10.1038/s43586-022-00174-y · Cited by 1,001 · see citing works
“Adapted from ref.(131), Springer Nature Limited.”
Self-citationCancer modeling meets human organoid technology
Tuveson, D., & Clevers, H. (2019) · Science · doi:10.1126/science.aaw6985 · Cited by 935 · see citing works
Tumor Evolution and Drug Response in Patient-Derived Organoid Models of Bladder Cancer
Lee, S. H., Hu, W., Matulay, J. T., Silva, M. V., Owczarek, T. B., Kim, K., Chua, C. W., Barlow, L. J., Kandoth, C., Williams, A. B., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.017 · Cited by 873 · see citing works
Long-Term Expansion of Functional Mouse and Human Hepatocytes as 3D Organoids
Hu, H., Gehart, H., Artegiani, B., LÖpez-Iglesias, C., Dekkers, F., Basak, O., van Es, J., Chuva de Sousa Lopes, S. M., Begthel, H., Korving, J., et al. (2018) · Cell · doi:10.1016/j.cell.2018.11.013 · Cited by 837 · see citing works
Patient-derived lung cancer organoids as in vitro cancer models for therapeutic screening
Kim, M., Mun, H., Sung, C. O., Cho, E. J., Jeon, H.-J., Chun, S.-M., Jung, D. J., Shin, T. H., Jeong, G. S., Kim, D. K., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11867-6 · Cited by 812 · see citing works
Xuan, L., Ju, Z., Skonieczna, M., Zhou, P., & Huang, R. (2023) · MedComm · doi:10.1002/mco2.327 · Cited by 863 · see citing works
Patient-Derived Organoids Predict Chemoradiation Responses of Locally Advanced Rectal Cancer
Yao, Y., Xu, X., Yang, L., Zhu, J., Wan, J., Shen, L., Xia, F., Fu, G., Deng, Y., Pan, M., et al. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2019.10.010 · Cited by 755 · see citing works
Establishment of patient-derived cancer organoids for drug-screening applications
Driehuis, E., Kretzschmar, K., & Clevers, H. C. (2020) · Nature Protocols · doi:10.1038/s41596-020-0379-4 · Cited by 656 · see citing works
Stem cell fate in cancer growth, progression and therapy resistance
Lytle, N. K., Barber, A. G., & Reya, T. (2018) · Nature reviews. Cancer · doi:10.1038/s41568-018-0056-x · Cited by 645 · see citing works
Advances in molecular classification and precision oncology in hepatocellular carcinoma
Rebouissou, S., & Nault, J. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2019.08.017 · Cited by 580 · see citing works
Corrò, C., Novellasdemunt, L., & Li, V. S. W. (2020) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00120.2020 · Cited by 561 · see citing works
Modeling Steatohepatitis in Humans with Pluripotent Stem Cell-Derived Organoids
Ouchi, R., Togo, S., Kimura, M., Shinozawa, T., Koido, M., Koike, H., Thompson, W., Karns, R. A., Mayhew, C. N., McGrath, P. S., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.05.007 · Cited by 537 · see citing works
High-resolution 3D imaging of fixed and cleared organoids
Dekkers, J. F., Alieva, M., Wellens, L. M., Ariese, H. C., Jamieson, P. R., Vonk, A. M., Amatngalim, G. D., Hu, H., Oost, K. C., Snippert, H. J. G., et al. (2019) · Nature Protocols · doi:10.1038/s41596-019-0160-8 · Cited by 534 · see citing works
Human Organoids: Tools for Understanding Biology and Treating Diseases
Schutgens, F., & Clevers, H. C. (2019) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-012419-032611 · Cited by 506 · see citing works
Boretto, M., Maenhoudt, N., Luo, X., Hennes, A., Boeckx, B., Bui, B. N., Heremans, R., Perneel, L., Kobayashi, H., Zundert, I. V., et al. (2019) · Nature Cell Biology · doi:10.1038/s41556-019-0360-z · Cited by 507 · see citing works
Human organoids in basic research and clinical applications
Tang, X., Wu, S., Wang, D., Chu, C., Hong, Y., Tao, M., Hu, H., Xu, M., Guo, X., & Liu, Y. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01024-9 · Cited by 424 · see citing works
“By modifying the combination of growth factors and cell isolation procedures, researchers can rapidly alter the 3D culture system to generate multiple kinds of human normal and cancerous organoids, such as brain,(13,14) colon,(15) stomach,(16) and liver organoids.(17,18) In this review, we discuss recent advances in o…”
BackgroundOrganoid and Spheroid Tumor Models: Techniques and Applications
Gunti, S., Hoke, A. T. K., Vu, K., & London, N. R. (2021) · Cancers · doi:10.3390/cancers13040874 · Cited by 492 · see citing works
Organoid Models of Human Liver Cancers Derived from Tumor Needle Biopsies
Nuciforo, S., Fofana, I., Matter, M. S., Blumer, T., Calabrese, D., Boldanova, T., Piscuoglio, S., Wieland, S., Ringnalda, F., Schwank, G., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.07.001 · Cited by 473 · see citing works
Next-generation cancer organoids
LeSavage, B. L., Suhar, R. A., Broguière, N., Lütolf, M. P., & Heilshorn, S. C. (2021) · Nature Materials · doi:10.1038/s41563-021-01057-5 · Cited by 462 · see citing works
Precision treatment in advanced hepatocellular carcinoma
Yang, X., Yang, C. G., Zhang, S., Geng, H., Zhu, A. X., Bernards, R., Qin, W., Fan, J., Wang, C., & Gao, Q. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.01.007 · Cited by 444 · see citing works
Xenograft and organoid model systems in cancer research
Bleijs, M., van de Wetering, M., Clevers, H., & Drost, J. (2019) · The EMBO Journal · doi:10.15252/embj.2019101654 · Cited by 400 · see citing works
“…gastric (Nanki et al , 2018; Yan et al , 2018), lung (Sachs et al , 2019), oesophageal (Li et al , 2018), bladder (Lee et al , 2018; Mullenders et al , 2019), ovarian (Kopper et al , 2019), kidney (Schutgens et al , 2019) and liver (Broutier et al , 2017; Li et al , 2019) tumour tissue (Fig 3).”
Organoid Models of Tumor Immunology
Yuki, K., Cheng, N., Nakano, M., & Kuo, C. J. (2020) · Trends in Immunology · doi:10.1016/j.it.2020.06.010 · Cited by 401 · see citing works
“Organoid biobanks have been established from multiple types of cancer, including colon [30,34,40,63,64], rectum, stomach [31,65], pancreas [66], liver [67,68], breast [32], ovary [69,70], and prostate [71], with distribution through entities such as the Human Cancer Models Initiative (HCMI)i.”
BackgroundThe role of gut microbiota in cancer treatment: friend or foe?
Cheng, W. Y., Wu, C.-Y., & Yu, J. (2020) · Gut · doi:10.1136/gutjnl-2020-321153 · Cited by 384 · see citing works
Tumor microenvironment: barrier or opportunity towards effective cancer therapy
Tiwari, A., Trivedi, R., & Lin, S. (2022) · Journal of Biomedical Science · doi:10.1186/s12929-022-00866-3 · Cited by 391 · see citing works
Disease modelling in human organoids
Lancaster, M. A., & Huch, M. (2019) · Disease Models & Mechanisms · doi:10.1242/dmm.039347 · Cited by 379 · see citing works
“Since these seminal papers, altered protocols have enabled the establishment of liver models from different species from rat to dog (Nantasanti et al., 2015; Kuijk et al., 2016; Kruitwagen et al., 2017) , as well as human disease models ranging from alpha-1-antitrypsin (A1AT) deficiency and Alagille syndrome to polycy…”
Self-citationOrganoids in immunological research
Bar-Ephraim, Y. E., Kretzschmar, K., & Clevers, H. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-019-0248-y · Cited by 361 · see citing works
3D model for CAR‐mediated cytotoxicity using patient‐derived colorectal cancer organoids
Schnalzger, T. E., de Groot, M. H., Zhang, C., Mosa, M. H., Michels, B. E., Röder, J., Darvishi, T., Wels, W. S., & Farin, H. F. (2019) · The EMBO Journal · doi:10.15252/embj.2018100928 · Cited by 354 · see citing works
“…for other major cancer entities such as carcinomas of the breast, prostate, stomach, pancreas, and liver (Gao et al , 2014; Boj et al , 2015; Broutier et al , 2017; Sachs et al , 2018; Seidlitz et al , 2018), the co-culture work-flows established herein may provide a valuable tool for…”
Liver organoids: from basic research to therapeutic applications
Prior, N., Inacio, P., & Huch, M. (2019) · Gut · doi:10.1136/gutjnl-2019-319256 · Cited by 356 · see citing works
Self-citationOrganoid technology and applications in cancer research
Xu, H., Lyu, X., Yi, M., Zhao, W., Song, Y., & Wu, K. (2018) · Journal of Hematology & Oncology · doi:10.1186/s13045-018-0662-9 · Cited by 350 · see citing works
“For expression profile, alfa-fetoprotein and glypican-3, markers of HCC, were upregulated in HCC tumoroids but the levels of CC markers remained low [34].”
BackgroundMethodInfluentialTumor organoids: Opportunities and challenges to guide precision medicine
Veninga, V., & Voest, E. E. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.07.020 · Cited by 339 · see citing works
Inflammatory Cytokine TNFα Promotes the Long-Term Expansion of Primary Hepatocytes in 3D Culture
Peng, W. C., Logan, C. Y., Fish, M., Anbarchian, T., Aguisanda, F., Álvarez-Varela, A., Wu, P., Jin, Y., Zhu, J., Li, B., et al. (2018) · Cell · doi:10.1016/j.cell.2018.11.012 · Cited by 331 · see citing works
Precision Medicine: Disease Subtyping and Tailored Treatment
Wang, R. C., & Wang, Z. (2023) · Cancers · doi:10.3390/cancers15153837 · Cited by 337 · see citing works
“The identification of the Lgr5+ adult stem cell population within the intestinal crypt [144] and the subsequent development of the growth factor recipe for human intestinal organoids [145] made the development of organoids possible and opened the way to the generation of organoids from many tissues, including the colo…”
BackgroundLi, X., Francies, H. E., Secrier, M., Perner, J., Miremadi, A., Galeano-Dalmau, N., Barendt, W. J., Letchford, L., Leyden, G. M., Goffin, E. K., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05190-9 · Cited by 316 · see citing works
Self-citationOrganoid Cultures as Preclinical Models of Non–Small Cell Lung Cancer
Shi, R., Radulovich, N., Ng, C., Liu, N., Notsuda, H., Cabanero, M., Martins-Filho, S. N., Raghavan, V., Li, Q., Mer, A. S., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-1376 · Cited by 316 · see citing works
“They have been proposed to be better in vitro models than 2D cell lines due to higher rates of preservation of key histologic and molecular traits of their parental tumors (14, 15).”
BackgroundBuilding consensus on definition and nomenclature of hepatic, pancreatic, and biliary organoids
Marsee, A., Roos, F. J. M., Verstegen, M. M. A., Marsee, A., Roos, F., Verstegen, M., Clevers, H., Vallier, L., Takebe, T., Huch, M., et al. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2021.04.005 · Cited by 310 · see citing works
Self-citationAn organoid biobank for childhood kidney cancers that captures disease and tissue heterogeneity
Calandrini, C., Schutgens, F., Oka, R., Margaritis, T., Candelli, T., Mathijsen, L., Ammerlaan, C. M. E., van Ineveld, R. L., Derakhshan, S., de Haan, S., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15155-6 · Cited by 304 · see citing works
Tang, M., Xie, Q., Gimple, R. C., Zhong, Z., Tam, T., Tian, J., Kidwell, R. L., Wu, Q., Prager, B. C., Qiu, Z., et al. (2020) · Cell Research · doi:10.1038/s41422-020-0338-1 · Cited by 298 · see citing works
Growth of Epithelial Organoids in a Defined Hydrogel
Broguiere, N., Isenmann, L., Hirt, C., Ringel, T., Placzek, S., Cavalli, E., Ringnalda, F., Villiger, L., Züllig, R., Lehmann, R., et al. (2018) · Advanced Materials · doi:10.1002/adma.201801621 · Cited by 282 · see citing works
Could 3D models of cancer enhance drug screening?
Brancato, V., Oliveira, J. M., Correlo, V. M., Reis, R. L., & Kundu, S. C. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.119744 · Cited by 283 · see citing works
Tumor organoids: applications in cancer modeling and potentials in precision medicine
Xu, H., Jiao, D., Liu, A., & Wu, K. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01278-4 · Cited by 286 · see citing works
Lung cancer organoids analyzed on microwell arrays predict drug responses of patients within a week
Hu, Y., Sui, X., Song, F., Li, Y., Li, K., Chen, Z., Yang, F., Chen, X., Zhang, Y., Wang, X., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22676-1 · Cited by 272 · see citing works
Organoids: The current status and biomedical applications
Yang, S., Hu, H., Kung, H., Zou, R.-Q., Dai, Y.-S., Hu, Y.-F., Wang, T., Lv, T., Yu, J., & Li, F. (2023) · MedComm · doi:10.1002/mco2.274 · Cited by 282 · see citing works
Aref, A. R., Campisi, M., Ivanova, E., Portell, A., Larios, D., Piel, B. P., Mathur, N., Zhou, C., Coakley, R. V., Bartels, A., et al. (2018) · Lab on a Chip · doi:10.1039/c8lc00322j · Cited by 265 · see citing works
Modeling neoplastic disease with spheroids and organoids
Zanoni, M., Cortesi, M., Zamagni, A., Arienti, C., Pignatta, S., & Tesei, A. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00931-0 · Cited by 265 · see citing works
“3) including colon [121–125], breast [118, 126], liver [127, 128], lung [129, 130], pancreas [131, 132], endometrium [133], stomach [119, 134, 135], prostate [136, 137], ovary [138], bladder [139, 140], kidney [141–143], brain [144, 145], bone [146, 147], and esophagus [148, 149].”
BackgroundTargeted therapy for hepatocellular carcinoma: Challenges and opportunities
Chen, S., Cao, Q., Wen, W., & Wang, H. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.114428 · Cited by 253 · see citing works
Ongoing chromosomal instability and karyotype evolution in human colorectal cancer organoids
Bolhaqueiro, A. C. F., Ponsioen, B., Bakker, B., Klaasen, S. J., Küçükköse, E., van Jaarsveld, R. H., Vivié, J., Verlaan-Klink, I., Hami, N., Spierings, D. C. J., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0399-6 · Cited by 240 · see citing works
Deng, J., Wei, W., Chen, Z., Lin, B., Zhao, W., Luo, Y., & Zhang, X. (2019) · Micromachines · doi:10.3390/mi10100676 · Cited by 232 · see citing works
“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].”
MethodBeshiri, M. L., Tice, C. M., Tran, C., Nguyen, H. M., Sowalsky, A. G., Agarwal, S., Jansson, K. H., Yang, Q., McGowen, K. M., Yin, J., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-0409 · Cited by 228 · see citing works
“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 227 · see citing works
Strategies to reduce the risks of mRNA drug and vaccine toxicity
Bitounis, D., Jacquinet, E., Rogers, M. A., & Amiji, M. M. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00859-3 · Cited by 237 · see citing works
“There are now reports of human organoids that simulate human organs and even organ-specific diseases, such as hepatocellular cholangiocarcinoma 220 or alveoli that mimic the pathophysiology of cystic fibrosis 221 .”
Basic principles of biobanking: from biological samples to precision medicine for patients
Annaratone, L., Palma, G. D., Bonizzi, G., Sapino, A., Botti, G., Berrino, E., Mannelli, C., Arcella, P., Martino, S. D., Steffan, A., et al. (2021) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-021-03151-0 · Cited by 227 · see citing works
Bioengineering Approaches for the Advanced Organoid Research
Yi, S. A., Zhang, Y., Rathnam, C., Pongkulapa, T., & Lee, K. (2021) · Advanced Materials · doi:10.1002/adma.202007949 · Cited by 218 · see citing works
Probing the Tumor Suppressor Function of BAP1 in CRISPR-Engineered Human Liver Organoids
Artegiani, B., van Voorthuijsen, L., Lindeboom, R. G. H., Seinstra, D., Heo, I., Tapia, P., López-Iglesias, C., Postrach, D., Dayton, T., Oka, R., et al. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2019.04.017 · Cited by 218 · see citing works
Thorel, L., Perréard, M., Florent, R., Divoux, J., Coffy, S., Vincent, A., Gaggioli, C., Guasch, G., Gidrol, X., Weiswald, L., et al. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01272-5 · Cited by 228 · see citing works
“For instance, PDTOs and tumor are comparable in terms of histology 18 and genetics 19 and display clonal evolution in culture 20 .”
BackgroundJacob, F., Ming, G., & Song, H. (2020) · Nature Protocols · doi:10.1038/s41596-020-0402-9 · Cited by 216 · see citing works
Human primary liver cancer organoids reveal intratumor and interpatient drug response heterogeneity
Li, L., Knútsdóttir, H., Hui, K., Weiss, M. J., He, J. P., Philosophe, B., Cameron, A. M., Wolfgang, C. L., Pawlik, T. M., Ghiaur, G., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.121490 · Cited by 216 · see citing works
“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 · see citing works
Clinical applications of human organoids
Verstegen, M. M. A., Coppes, R. P., Béghin, A., Coppi, P. D., Gerli, M., de Graeff, N., Pan, Q., Saito, Y., Shi, S., ZADPOOR, A. A., et al. (2025) · Nature Medicine · doi:10.1038/s41591-024-03489-3 · Cited by 228 · see citing works
“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.”
Self-citationWang, S., Wang, X., Tan, Z., Su, Y., Liu, J., Chang, M., Yan, F., Chen, J., Chen, T., Li, C., et al. (2019) · Cell Research · doi:10.1038/s41422-019-0242-8 · Cited by 211 · see citing works
Liu, J., Li, P., Wang, L., Li, M., Ge, Z., Noordam, L., Lieshout, R., Verstegen, M. M. A., Ma, B., Su, J., et al. (2020) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2020.09.003 · Cited by 211 · see citing works
“We established 6 mouse tumor organoids from carcinogen Nnitrosodiethylamine (DEN)-induced mouse liver tumors and 4 human CCA tumor organoids from resected patient CCA tumors as previously described.(4,5) CAFs were isolated and cultured from DEN-induced liver tumors of red fluorescence-expressing Rosa 26-membrane tomat…”
BackgroundMethodSelf-citationHu, B., Yu, M., Ma, X., Sun, J., Liu, C., Wang, C., Wu, S., Fu, P., Yang, Z. F., He, Y., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1022 · Cited by 209 · see citing works
Microfluidics for Drug Development: From Synthesis to Evaluation
Liu, Y., Sun, L., Zhang, H., Shang, L., & Zhao, Y. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.0c01289 · Cited by 209 · see citing works
A Pharmacogenomic Landscape in Human Liver Cancers
Qiu, Z., Li, H., Zhang, Z., Zhu, Z., He, S., Wang, X., Wang, P., Qin, J., Zhuang, L., Wang, W., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.07.001 · Cited by 202 · see citing works
“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 207 · see citing works
Mo, S., Tang, P., Luo, W., Zhang, L., Li, Y., Hu, X., Ma, X., Chen, Y., Bao, Y., He, X., et al. (2022) · Advanced Science · doi:10.1002/advs.202204097 · Cited by 198 · see citing works
Emerging organoid models: leaping forward in cancer research
Fan, H., Demirci, U., & Chen, P. (2019) · Journal of Hematology & Oncology · doi:10.1186/s13045-019-0832-4 · Cited by 199 · see citing works
“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 · see citing works
“The loss of three mutations in EOCO_11 organoids (Figure 2G) may point to a selection of (a) subclone(s) in this particular organoid line (as also reported for other cancer-derived organoids; Boretto et al., 2019; Broutier et al., 2017).”
BackgroundOrganoid models of gastrointestinal cancers in basic and translational research
Lau, H. C.-H., Kranenburg, O., Xiao, H., & Yu, J. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0255-2 · Cited by 195 · see citing works
van der Meer, D., Barthorpe, S., Yang, W., Lightfoot, H., Hall, C., Gilbert, J., Francies, H. E., & Garnett, M. J. (2019) · Nucleic Acids Research · doi:10.1093/nar/gky872 · Cited by 195 · see citing works
Self-citationUse and application of 3D-organoid technology
Artegiani, B., & Clevers, H. C. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy187 · Cited by 190 · see citing works
Galan, E. A., Zhao, H., Wang, X., Dai, Q., Huck, W. T. S., & Ma, S. (2020) · Matter · doi:10.1016/j.matt.2020.08.034 · Cited by 192 · see citing works
Applications of organoids for cancer biology and precision medicine
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Promises and challenges of organoid-guided precision medicine
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Magré, L., Verstegen, M. M. A., Buschow, S. I., van der Laan, L. J. W., Peppelenbosch, M. P., & Desai, J. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-006290 · Cited by 192 · see citing works
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Xu, H., Jiao, Y., Qin, S., Zhao, W., Chu, Q., & Wu, K. (2018) · Experimental Hematology and Oncology · doi:10.1186/s40164-018-0122-9 · Cited by 184 · see citing works
Cai, J., Song, L., Zhang, F., Wu, S., Zhu, G., Zhang, P., Chen, S., Du, J.-X., Wang, B., Cai, Y., et al. (2024) · 癌症：英文版 · doi:10.1002/cac2.12607 · Cited by 193 · see citing works
“However, traditional PDOs exhibit limited similarities to the TME [50].”
The landscape of gene mutations in cirrhosis and hepatocellular carcinoma
Müller, M., Bird, T. G., & Nault, J. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.01.019 · Cited by 178 · see citing works
“systems exist for human hepatocyte culture both in 2D and as 3D organoids [53, 98-104] with the”
BackgroundA one-stop microfluidic-based lung cancer organoid culture platform for testing drug sensitivity
Jung, D. J., Shin, T. H., Kim, M., Sung, C. O., Jang, S. J., & Jeong, G. S. (2019) · Lab on a Chip · doi:10.1039/c9lc00496c · Cited by 178 · see citing works
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“Liver CSC-derived NCI-Approved Oncology Drugs Set VII 129 5 Matrigel (60) Liver CSC-dervied Target-know inhibitor + chemotherapy drugs 29 5 BME (61)”
BackgroundIn Vitro three-dimensional (3D) cell culture tools for spheroid and organoid models
Lee, S., Koo, I.-S., Hwang, H. J., & Lee, D. W. (2023) · SLAS DISCOVERY · doi:10.1016/j.slasd.2023.03.006 · Cited by 184 · see citing works
Tumor heterogeneity: preclinical models, emerging technologies, and future applications
Proietto, M., Crippa, M., Damiani, C., Pasquale, V., Sacco, E., Vanoni, M., & Gilardi, M. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1164535 · Cited by 180 · see citing works
“, breast cancer (70), liver cancer (71, 72), gastric cancer (73), colorectal cancer (74), prostate cancer (75), and pancreatic cancer (76–78).”
BackgroundHarnessing big ‘omics’ data and AI for drug discovery in hepatocellular carcinoma
Chen, B., Garmire, L., Calvisi, D. F., Chua, M.-S., Kelley, R. K., & Chen, X. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0240-9 · Cited by 154 · see citing works
Somatic cell-derived organoids as prototypes of human epithelial tissues and diseases
Fujii, M., & Sato, T. (2020) · Nature Materials · doi:10.1038/s41563-020-0754-0 · Cited by 165 · see citing works
Organoids to model liver disease
Nuciforo, S., & Heim, M. H. (2021) · JHEP Reports · doi:10.1016/j.jhepr.2020.100198 · Cited by 164 · see citing works
Patient-derived organoids in precision cancer medicine
Tong, L., Cui, W., Zhang, B., Fonseca, P., Zhao, Q. C., Zhang, P., Xu, B., Zhang, Q., Li, Z., Seashore-Ludlow, B. A., et al. (2024) · Med · doi:10.1016/j.medj.2024.08.010 · Cited by 173 · see citing works
Qu, J., Kalyani, F. S., Liu, L., Cheng, T., & Chen, L. (2021) · 癌症：英文版 · doi:10.1002/cac2.12224 · Cited by 166 · see citing works
“Three major types of liver cancer organoids, namely, hepatocellular carcinoma (HCC), cholangiocarcinoma, and HCC combined with cholangiocarcinoma, have been established [29] using typical human liver organoid culture medium and tumoroid-specific culture medium (Table 1).”
BackgroundOrganoid cultures for cancer modeling
Yan, H. H. N., Chan, A., Lai, F. P.-L., & Leung, S. Y. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.05.012 · Cited by 163 · see citing works
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Concise Review: Current Status of Three-Dimensional Organoids as Preclinical Models
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Promising Applications of Tumor Spheroids and Organoids for Personalized Medicine
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“Organoid cultures of hepatocellular carcinoma and cholangiocarcinoma retained the histological architecture, gene expression and genomic landscape of the original tumor [91].”
BackgroundInfluentialSorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity
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“The use of 3-dimensional cultures, spheroids, and organoids would allow investigation of drug response considering other organ components and characteristics (3D- architecture, cell-to-cell, cell-to-matrix interactions, cellular heterogeneity, and tumor microenvironment), as reviewed in [129].”
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).”
- 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
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