Liver metastatic cancer organoid models: From mechanistic insights to precision medicine
Metastasis is a primary cause of cancer-related mortality, and the liver is the most common site of tumor metastasis. The molecular heterogeneity and complex tumor microenvironment of liver metastases remain major barriers contributing to clinical treatment failure. The dearth of accurate metastatic liver tumor models leads to a paucity of understanding regarding the mechanisms of liver metastasis and limits the exploration of novel therapeutic approaches. Patient-derived organoids provide a three-dimensional, tissue-engineered, cell-based in vitro model that reproduces the complex structure and function of the corresponding in vivo tissue. The advent of this personalized paradigm, tailored to the specific needs of individual patients, has enabled the translation of foundational research into clinical applications. This review provides a comprehensive summary of various methods for culturing liver metastatic cancer organoids, highlighting the novel findings and clinical applicability of organoids in liver metastasis research. It also discusses current research achievements and recent advances in liver metastatic cancer organoids.
- Tsilimigras DI, Brodt P, Clavien PA, et al. Liver metastases. Nat Rev Dis Primer. 2021;7(1):27. doi: 10.1038/s41572-021-00261-6
- Gast CE, Silk AD, Zarour L, et al. Cell fusion potentiates tumor heterogeneity and reveals circulating hybrid cells that correlate with stage and survival. Sci Adv. 2018;4(9):eaat7828. doi: 10.1126/sciadv.aat7828
- Zhao Z, Chen X, Dowbaj AM, et al. Organoids. Nat Rev Methods Primer. 2022;2(1):94. doi: 10.1038/s43586-022-00174-y
- Crespo M, Vilar E, Tsai SY, et al. Colonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing. Nat Med. 2017;23(7):878-884. doi: 10.1038/nm.4355
- Hofer M, Lutolf MP. Engineering organoids. Nat Rev Mater. 2021;6(5):402-420. doi: 10.1038/s41578-021-00279-y
- Wang Z, McWilliams-Koeppen HP, Reza H, et al. 3D-organoid culture supports differentiation of human CAR+ iPSCs into highly functional CAR T cells. Cell Stem Cell. 2022;29(4):515-527.e8. doi: 10.1016/j.stem.2022.02.009
- Kim J, Koo BK, Knoblich JA. Human organoids: Model systems for human biology and medicine. Nat Rev Mol Cell Biol. 2020;21(10):571-584. doi: 10.1038/s41580-020-0259-3
- Han X, Cai C, Deng W, et al. Landscape of human organoids: Ideal model in clinics and research. Innov. 2024;5(3):100620. doi: 10.1016/j.xinn.2024.100620
- Borrelli C, Roberts M, Eletto D, et al. In vivo interaction screening reveals liver-derived constraints to metastasis. Nature. 2024;632(8024):411-418. doi: 10.1038/s41586-024-07715-3
- Gerstberger S, Jiang Q, Ganesh K. Metastasis. Cell. 2023;186(8):1564-1579. doi: 10.1016/j.cell.2023.03.003
- Huang Y, Hong W, Wei X. The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis. J Hematol OncolJ Hematol Oncol. 2022;15(1):129. doi: 10.1186/s13045-022-01347-8
- Zhang X, Sai B, Wang F, et al. Hypoxic BMSC-derived exosomal miRNAs promote metastasis of lung cancer cells via STAT3-induced EMT. Mol Cancer. 2019;18(1):40. doi: 10.1186/s12943-019-0959-5
- Hu J, Tan P, Ishihara M, et al. Tumor heterogeneity in VHL drives metastasis in clear cell renal cell carcinoma. Signal Transduct Target Ther. 2023;8(1):155. doi: 10.1038/s41392-023-01362-2
- Qiu M, Wang J, Xia W, et al. Glypican-5 to suppress NSCLC metastasis and EMT process by blocking Wnt/β-catenin signaling pathway. J Clin Oncol. 2016;34(15 Suppl):e23014. doi: 10.1200/jco.2016.34.15_suppl.e23014
- Zheng X, Zhang X, Yu S. Organoids derived from metastatic cancers: Present and future. Heliyon. 2024;10(9):e30457. doi: 10.1016/j.heliyon.2024.e30457
- Puca L, Bareja R, Prandi D, et al. Patient derived organoids to model rare prostate cancer phenotypes. Nat Commun. 2018;9(1):2404. doi: 10.1038/s41467-018-04495-z
- Bruun J, Kryeziu K, Eide PW, et al. Patient-derived organoids from multiple colorectal cancer liver metastases reveal moderate intra-patient pharmacotranscriptomic heterogeneity. Clin Cancer Res. 2020;26(15):4107-4119. doi: 10.1158/1078-0432.CCR-19-3637
- Mo S, Tang P, Luo W, et al. Patient-derived organoids from colorectal cancer with paired liver metastasis reveal tumor heterogeneity and predict response to chemotherapy. Adv Sci. 2022;9(31):2204097. doi: 10.1002/advs.202204097
- Tan T, Mouradov D, Lee M, et al. Unified framework for patient-derived, tumor-organoid-based predictive testing of standard-of-care therapies in metastatic colorectal cancer. Cell Rep Med. 2023;4(12):101335. doi: 10.1016/j.xcrm.2023.101335
- Chen P, Zhang X, Ding R, et al. Patient-derived organoids can guide personalized-therapies for patients with advanced breast cancer. Adv Sci. 2021;8(22):2101176. doi: 10.1002/advs.202101176
- Yan Z, Ohuchida K, Fei S, et al. Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer-stromal interaction and metastasis. J Exp Clin Cancer Res. 2019;38(1):221. doi: 10.1186/s13046-019-1226-8
- Wang Z, Zhou L, Wang Y, et al. The CK1δ/ε-AES axis regulates tumorigenesis and metastasis in colorectal cancer. Theranostics. 2021;11(9):4421-4435. doi: 10.7150/thno.53901
- Zhou JM, Dai WX, Wang RJ, et al. Organoid modeling identifies USP3-AS1 as a novel promoter in colorectal cancer liver metastasis through increasing glucose-driven histone lactylation. Acta Pharmacol Sin. 2025;46:1404-1418. doi: 10.1038/s41401-024-01465-8
- Ouzounova M, Lee E, Piranlioglu R, et al. Monocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumour plasticity during metastatic cascade. Nat Commun. 2017;8(1):14979. doi: 10.1038/ncomms14979
- Gao Q, Li N, Pan Y, et al. Hepatocyte growth factor promotes melanoma metastasis through ubiquitin-specific peptidase 22-mediated integrins upregulation. Cancer Lett. 2024;604:217196. doi: 10.1016/j.canlet.2024.217196
- Igarashi R, Oda M, Okada R, et al. Generation of human adult hepatocyte organoids with metabolic functions. Nature. 2025;641(8065):1248-1257. doi: 10.1038/s41586-025-08861-y
- Liao Y, Chen Q, Liu L, et al. Amino acid is a major carbon source for hepatic lipogenesis. Cell Metab. 2024;36(11):2437-2448.e8. doi: 10.1016/j.cmet.2024.10.001
- Li T, Song X, Chen J, et al. Kupffer cell-derived IL6 promotes hepatocellular carcinoma metastasis via the JAK1-ACAP4 pathway. Int J Biol Sci. 2025;21:285-305. doi: 10.7150/ijbs.97109
- Nuciforo S, Fofana I, Matter MS, et al. Organoid models of human liver cancers derived from tumor needle biopsies. Cell Rep. 2018;24(5):1363-1376. doi: 10.1016/j.celrep.2018.07.001
- Cammareri P, Raponi M, Hong Y, et al. Loss of colonic fidelity enables multilineage plasticity and metastasis. Nature. 2025;644(8076):547-556. doi: 10.1038/s41586-025-09125-5
- Moorman AR, Benitez EK, Cambuli F, et al. Progressive plasticity during colorectal cancer metastasis. Nature. 2024;637:947-954. doi: 10.1038/s41586-024-08150-0
- Polak R, Zhang ET, Kuo CJ. Cancer organoids 2.0: Modelling the complexity of the tumour immune microenvironment. Nat Rev Cancer. 2024;24(8):523-539. doi: 10.1038/s41568-024-00706-6
- Neal JT, Li X, Zhu J, et al. Organoid modeling of the tumor immune microenvironment. Cell. 2018;175(7):1972-1988.e16. doi: 10.1016/j.cell.2018.11.021
- Sheng N, Shindo K, Ohuchida K, et al. TAK1 promotes an immunosuppressive tumor microenvironment through cancer-associated fibroblast phenotypic conversion in pancreatic ductal adenocarcinoma. Clin Cancer Res. 2024;30(22):5138-5153. doi: 10.1158/1078-0432.ccr-24-1004
- Esposito A, Agostini A, Quero G, et al. Colorectal cancer patients-derived immunity-organoid platform unveils cancer-specific tissue markers associated with immunotherapy resistance. Cell Death Dis. 2024;15(12):878. doi: 10.1038/s41419-024-07266-5
- Soldani C, De Simone G, Polidoro MA, et al. Riboflavin-LSD1 axis participates in the in vivo tumor-associated macrophage morphology in human colorectal liver metastases. Cancer Immunol Immunother. 2024;73(4):63. doi: 10.1007/s00262-024-03645-1
- Du Y, Lin Y, Gan L, et al. Potential crosstalk between SPP1 + TAMs and CD8 + exhausted T cells promotes an immunosuppressive environment in gastric metastatic cancer. J Transl Med. 2024;22(1):158. doi: 10.1186/s12967-023-04688-1
- Hua Y, Ma X, Zhao X, Wei X, Mu X, Zhang X. Characterization of metastasis-specific macrophages in colorectal cancer for prognosis prediction and immunometabolic remodeling. Sci Rep. 2024;14(1):26361. doi: 10.1038/s41598-024-77248-2
- Ainiwaer A, Qian Z, Wang J, Zhao Q, Lu Y. Single-cell analysis uncovers liver susceptibility to pancreatic cancer metastasis via myeloid cell characterization. Discov Oncol. 2024;15(1):696. doi: 10.1007/s12672-024-01566-0
- Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9(4):239-252. doi: 10.1038/nrc2618
- Feng Y, Qiao S, Chen J, et al. M2-type macrophages and cancer-associated fibroblasts combine to promote colorectal cancer liver metastases. OncoTargets Ther. 2024;17:243-260. doi: 10.2147/ott.s447502
- Astuti Y, Raymant M, Quaranta V, et al. Efferocytosis reprograms the tumor microenvironment to promote pancreatic cancer liver metastasis. Nat Cancer. 2024;5(5):774-790. doi: 10.1038/s43018-024-00731-2
- Chen C, Wang Z, Lin Q, et al. NAT10 promotes gastric cancer liver metastasis by modulation of M2 macrophage polarization and metastatic tumor cell hepatic adhesion. Adv Sci (Weinh). 12(15):2410263. doi: 10.1002/advs.202410263
- Liu K, Jing N, Wang D, et al. A novel mouse model for liver metastasis of prostate cancer reveals dynamic tumour-immune cell communication. Cell Prolif. 2021;54(7):e13056. doi: 10.1111/cpr.13056
- Lamprou M, Garcia AK, Suijkerbuijk SJE. Protocol for generating liver metastasis microtissues to decipher cellular interactions between metastatic intestinal cancer and liver tissue. STAR Protoc. 2025;6(1):103575. doi: 10.1016/j.xpro.2024.103575
- Abilez OJ, Yang H, Guan Y, et al. Gastruloids enable modeling of the earliest stages of human cardiac and hepatic vascularization. Science. 2025;388(6751):eadu9375. doi: 10.1126/science.adu9375
- Du Y, Wang YR, Bao QY, et al. Personalized vascularized tumor organoid-on-a-chip for tumor metastasis and therapeutic targeting assessment. Adv Mater. 2025;37(6):2412815. doi: 10.1002/adma.202412815
- Wakefield L, Agarwal S, Tanner K. Preclinical models for drug discovery for metastatic disease. Cell. 2023;186(8):1792-1813. doi: 10.1016/j.cell.2023.02.026
- Xiang T, Wang J, Li H. Current applications of intestinal organoids: A review. Stem Cell Res Ther. 2024;15(1):155. doi: 10.1186/s13287-024-03768-3
- Veninga V, Voest EE. Tumor organoids: Opportunities and challenges to guide precision medicine. Cancer Cell. 2021;39(9):1190-1201. doi: 10.1016/j.ccell.2021.07.020
- Eng C, Yoshino T, Ruíz-García E, et al. Colorectal cancer. Lancet. 2024;404(10449):294-310. doi: 10.1016/S0140-6736(24)00360-X
- Lentz RW, Messersmith WA. Transarterial radioembolization in patients with unresectable colorectal cancer liver metastases. J Clin Oncol. 2021;39(35):3887-3889. doi: 10.1200/JCO.21.01993
- Engstrand J, Nilsson H, Strömberg C, Jonas E, Freedman J. Colorectal cancer liver metastases - a population-based study on incidence, management and survival. BMC Cancer. 2018;18(1):78. doi: 10.1186/s12885-017-3925-x
- Shasha T, Gruijs M, Van Egmond M. Mechanisms of colorectal liver metastasis development. Cell Mol Life Sci. 2022;79(12):607. doi: 10.1007/s00018-022-04630-6
- Cioce M, Fumagalli MR, Donzelli S, et al. Interrogating colorectal cancer metastasis to liver: a search for clinically viable compounds and mechanistic insights in colorectal cancer patient derived organoids. J Exp Clin Cancer Res. 2023;42(1):170. doi: 10.1186/s13046-023-02754-6
- Jian M, Ren L, He G, et al. A novel patient-derived organoids-based xenografts model for preclinical drug response testing in patients with colorectal liver metastases. J Transl Med. 2020;18(1):234. doi: 10.1186/s12967-020-02407-8
- Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the united states. Cancer Res. 2014;74(11):2913-2921. doi: 10.1158/0008-5472.can-14-0155
- Hess KR, Varadhachary GR, Taylor SH, et al. Metastatic patterns in adenocarcinoma. Cancer. 2006;106(7):1624-1633. doi: 10.1002/cncr.21778
- Jeong YJ, Knutsdottir H, Shojaeian F, et al. Morphology-guided transcriptomic analysis of human pancreatic cancer organoids reveals microenvironmental signals that enhance invasion. J Clin Invest. 2023;133(8):e162054. doi: 10.1172/JCI162054
- Antonucci L, Li N, Duran A, et al. Self-amplifying NRF2-EZH2 epigenetic loop converts KRAS-initiated progenitors to invasive pancreatic cancer. Nat Cancer. 2025;6(7):1263-1282. doi: 10.1038/s43018-025-01003-3
- Boilève A, Cartry J, Goudarzi N, et al. Organoids for functional precision medicine in advanced pancreatic cancer. Gastroenterology. 2024;167(5):961-976.e13. doi: 10.1053/j.gastro.2024.05.032
- Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17-48. doi: 10.3322/caac.21763
- Lee J, Choi M, Joe S, Shin K, Lee SH, Lee A. Growth pattern of hepatic metastasis as a prognostic index reflecting liver metastasis-associated survival in breast cancer liver metastasis. J Clin Med. 2022;11(10):2852. doi: 10.3390/jcm11102852
- Harbeck N, Penault-Llorca F, Cortes J, et al. Breast cancer. Nat Rev Dis Primer. 2019;5(1):66. doi: 10.1038/s41572-019-0111-2
- Gaglia G, Burger ML, Ritch CC, et al. Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma. Cancer Cell. 2023;41(5):871-886.e10. doi: 10.1016/j.ccell.2023.03.015
- Sachs N, Ligt JD, Kopper O, et al. A living biobank of breast cancer organoids captures disease heterogeneity. Cell. 2018;172(1):373-386.e10. doi: 10.1016/j.cell.2017.11.010
- Harbeck N, Gnant M. Breast cancer. Lancet. 2017; 389(10074):1134-1150. doi: 10.1016/S0140-6736(16)31891-8
- Fusella F, Seclì L, Busso E, et al. The IKK/NF-κB signaling pathway requires Morgana to drive breast cancer metastasis. Nat Commun. 2017;8(1):1636. doi: 10.1038/s41467-017-01829-1
- Lin Y yi, Gao H fei, Li H, et al. Clinical efficacy of tumor organoid-guided cancer therapy for locally advanced unresectable or metastatic breast cancer. Int J Cancer. 2024;155(4):697-709. doi: 10.1002/ijc.34945
- Harter MF, Recaldin T, Gerard R, et al. Analysis of off-tumour toxicities of T-cell-engaging bispecific antibodies via donor-matched intestinal organoids and tumouroids. Nat Biomed Eng. 2024;8(4):345-360. doi: 10.1038/s41551-023-01156-5
- Geurts MH, Gandhi S, Boretto MG, et al. One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids. Nat Commun. 2023;14(1):4998. doi: 10.1038/s41467-023-40701-3
- Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS. Lung cancer. Lancet. 2021;398(10299):535-554. doi: 10.1016/S0140-6736(21)00312-3
- Xie S, Wu Z, Qi Y, Wu B, Zhu X. The metastasizing mechanisms of lung cancer: Recent advances and therapeutic challenges. Biomed Pharmacother. 2021;138:111450. doi: 10.1016/j.biopha.2021.111450
- Leiter A, Veluswamy RR, Wisnivesky JP. The global burden of lung cancer: Current status and future trends. Nat Rev Clin Oncol. 2023;20(9):624-639. doi: 10.1038/s41571-023-00798-3
- Li S, Qu Y, Liu L, et al. Comparative proteomic profiling of plasma exosomes in lung cancer cases of liver and brain metastasis. Cell Biosci. 2023;13(1):180. doi: 10.1186/s13578-023-01112-5
- Salvatierra A, Baamonde C, Llamas JM, Cruz F, Lopez-Pujol J. Extrathoracic staging of bronchogenic carcinoma. Chest. 1990;97(5):1052-1058. doi: 10.1378/chest.97.5.1052
- Gibert-Ramos A, Sanfeliu-Redondo D, Aristu-Zabalza P, et al. The hepatic sinusoid in chronic liver disease: The optimal milieu for cancer. Cancers. 2021;13(22):5719. doi: 10.3390/cancers13225719
- Dasgupta A, Lim AR, Ghajar CM. Circulating and disseminated tumor cells: Harbingers or initiators of metastasis? Mol Oncol. 2017;11(1):40-61. doi: 10.1002/1878-0261.12022
- Li J, Liu D, Gao Z, et al. Construction of a metastasis model for liver cancer spheroids to hepatobiliary organoids facilitated by holographic acoustic tweezers. Cell Rep Phys Sci. 2025;6(6):102604. doi: 10.1016/j.xcrp.2025.102604
- Liu Y, Lankadasari M, Rosiene J, et al. Modeling lung adenocarcinoma metastases using patient-derived organoids. Cell Rep Med. 2024;5(10):101777. doi: 10.1016/j.xcrm.2024.101777
- Lou L, Peng K, Ouyang S, et al. Periostin-mediated NOTCH1 activation between tumor cells and HSCs crosstalk promotes liver metastasis of small cell lung cancer. J Exp Clin Cancer Res. 2025;44(1):6. doi: 10.1186/s13046-024-03266-7
- Garbe C, Amaral T, Peris K, et al. European consensus-based interdisciplinary guideline for melanoma. Part 2: Treatment - update 2022. Eur J Cancer. 2022;170:256-284. doi: 10.1016/j.ejca.2022.04.018
- Blay JY, Devin Q, Duffaud F, et al. Discontinuation versus continuation of imatinib in patients with advanced gastrointestinal stromal tumours (BFR14): Exploratory long-term follow-up of an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2024;25(9):1163-1175. doi: 10.1016/S1470-2045(24)00318-8
- Foster DS, Jensen R, Norton JA. Management of liver neuroendocrine tumors in 2018. JAMA Oncol. 2018;4(11):1605-1606. doi: 10.1001/jamaoncol.2018.3035
- Kim SY, Kim SM, Lim S, et al. Modeling clinical responses to targeted therapies by patient-derived organoids of advanced lung adenocarcinoma. Clin Cancer Res. 2021;27(15):4397-4409. doi: 10.1158/1078-0432.ccr-20-5026
- Kan L, Yu Y, Wang Y, et al. The application of organoids in investigating immune evasion in the microenvironment of gastric cancer and screening novel drug candidates. Mol Cancer. 2025;24(1):125. doi: 10.1186/s12943-025-02328-4
- Sljukic A, Green Jenkinson J, Niksic A, Prior N, Huch M. Advances in liver and pancreas organoids: How far we have come and where we go next. Nat Rev Gastroenterol Hepatol. 2025;. doi: 10.1038/s41575-025-01116-1
- Garvalov BK, Ertürk A. Seeing whole-tumour heterogeneity. Nat Biomed Eng. 2017;1(10):772-774. doi: 10.1038/s41551-017-0150-5
- Pe’er D, Ogawa S, Elhanani O, Keren L, Oliver TG, Wedge D. Tumor heterogeneity. Cancer Cell. 2021;39(8):1015-1017. doi: 10.1016/j.ccell.2021.07.009
- Huang XZ, Pang MJ, Li JY, et al. Single-cell sequencing of ascites fluid illustrates heterogeneity and therapy-induced evolution during gastric cancer peritoneal metastasis. Nat Commun. 2023;14(1):822. doi: 10.1038/s41467-023-36310-9
- Barkley D, Moncada R, Pour M, et al. Cancer cell states recur across tumor types and form specific interactions with the tumor microenvironment. Nat Genet. 2022;54(8):1192-1201. doi: 10.1038/s41588-022-01141-9
- Xu J, Liao K, Yang X, Wu C, Wu W. Using single-cell sequencing technology to detect circulating tumor cells in solid tumors. Mol Cancer. 2021;20(1):104. doi: 10.1186/s12943-021-01392-w
- Zhou X, LeBleu VS, Fletcher-Sananikone E, et al. Vascular heterogeneity of tight junction Claudins guides organotropic metastasis. Nat Cancer. 2024;5(9):1371-1389. doi: 10.1038/s43018-024-00813-1
- Shi H, Tian H, Zhu T, et al. Single-cell sequencing depicts tumor architecture and empowers clinical decision in metastatic conjunctival melanoma. Cell Discov. 2024;10(1):63. doi: 10.1038/s41421-024-00683-y
- Matano M, Date S, Shimokawa M, et al. Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids. Nat Med. 2015;21(3):256-262. doi: 10.1038/nm.3802
- Chen M, Shan H, Tao Q, et al. Mimicking tumor metastasis using a transwell-integrated organoids-on-a-chip platform. Small. 2024;20(27):e2308525. doi: 10.1002/smll.202308525
- Kim J, Lee C, Kim I, et al. Three-dimensional human liver-chip emulating premetastatic niche formation by breast cancer-derived extracellular vesicles. ACS Nano. 2020;14(11):14971-14988. doi: 10.1021/acsnano.0c04778
