. 2023 Mar 6;29(3):643–669. doi: 10.3350/cmh.2022.0428

Table 2.

Primary liver cancer studies with tumoroid models

Reference	Tissue and cell source	Culture approach	Study highlight
Takai et al. [87], 2016	HCC and hepatoblastoma	3D culture with porous alginate scaffolds	3D cultured immortalized HCC cells form glandular epithelial spheroids with increased stemness marker expression compared to cells in monolayer culture.
Takai et al. [87], 2016	Immortalized HCC cell lines	3D culture with porous alginate scaffolds	The 3D cultured HCC cells exhibit greater tumorigenicity and metastasis potential when engrafted in vivo.
Broutier et al. [35], 2017	HCC, CCC, cHCC-CCC	ICO culture	The study demonstrated the feasibility of generating tumoroids from all three major liver cancer subtypes using the ICO culture approach.
Broutier et al. [35], 2017	Surgical resections	ICO culture	Tumoroid cultures retain histological architecture and the parental tumor’s mutational and gene expression profile.
Nuciforo et al. [89], 2018	HCC and CCC	ICO culture	The study demonstrates that the ICO culture method can also generate tumoroids from pre-surgical needle biopsy samples.
Nuciforo et al. [89], 2018	Tumor Needle Biopsies	ICO culture
Saltsman et al. [67], 2020	Hepatoblastoma	ICO culture	A lack of human models has hindered hepatoblastoma research progress. This study further highlighted the broad utility of the ICO culture approach to generate liver cancer models.
Saltsman et al. [67], 2020	Surgical resections	ICO culture
Li et al. [94], 2019	HCC and CCC	ICO culture	The study explores the potential of capturing intra-tumor heterogeneity (ITH) across large HCC tumors using the ICO culture method.
Li et al. [94], 2019	Multi-sections of a single large resected Tumor	ICO culture	Tumoroids generated from different sectors exhibit significant variation in drug resistance against a panel of 129 drugs.
Artegiani et al. [96], 2019	Healthy liver tissue	ICO culture	The study showed that oncogenic transformation of ICO using CRISPR-CAS9 mediated gene-editing enables modeling of cholangiocarcinoma development.
Yang et al. [98], 2022	Healthy fetal liver tissue	Hepatocyte organoid culture	The organoid culture approach enables the stable expansion of hepatocytes isolated from fetal liver tissue. Hippo-YAP activation induces malignant transformation of the fetal hepatocyte organoid into tumoroids resembling fetal hepatoblastoma.
Sun et al. [100], 2019	Human fibroblast	Trans-differentiated hepatic organoids	Overexpression of FOXA3, HNF1A, HNF4A, and SV40 large T antigen induces human fibroblast transdifferentiation to human-induced hepatic organoids (HiHeps). HiHeps can be employed to evaluate oncogenic effects and reveal mechanistic roles of known liver cancer driver genes.
Cao et al. [107], 2019	Tumor from mouse liver cancer models	ICO culture	Tumoroids derived from mouse liver cancer models can be expanded long-term and form tumors when engrafted. Tumors formed recapitulate the heterogeneity of liver cancer observed in cancer patients
Cao et al. [95], 2020	Tumor from mouse liver cancer models	ICO culture	Genetically engineered mouse models (GEMMs) can be used in parallel for investigating the mechanism of cancer initiation and progression.

HCC, hepatocellular carcinoma; CCC, cholangiocarcinoma; cHCC-CCC, combined hepatocellular cholangiocarcinoma; ICO, intrahepatic cholangiocyte organoids.