RARE DISEASE
Hepatoblastoma
Hepatoblastoma
Hepatoblastoma
Drug discovery
7
drugs
With orphan designations
Overview
Hepatoblastoma is the most common pediatric liver malignancy, predominantly affecting children under age 3, with strong associations with prematurity and very low birth weight [1][6]. Treatment combines surgical resection with cisplatin-based chemotherapy, achieving >90% survival in localized disease but <80% in metastatic cases [4][7]. Staging follows the PRETEXT/POSTTEXT system to guide resectability [6], while emerging therapies like HDAC inhibitors show promise for high-risk cases [8].
Categories: rare hepatic diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
1,608 drug discovery papers about Hepatoblastoma, with 5 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,608 drug discovery papers about Hepatoblastoma, with 5 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-18 | Novel 3D models for β-catenin-driven liver cancers.
Constitutive activation of β-catenin is a key feature in the pathogenesis of HCC and hepatoblastoma (HB). Activating alterations in the CTNNB1 gene and, to a lesser extent, inactivating alterations in the APC gene are observed in 30-40% of HCC cases and 80-90% of HB cases. For both tumours, therapeutic management remains suboptimal. Therefore, relevant experimental models are needed to improve our understanding and to test new therapeutic approaches. Liver organoids (n=17 mice) and tumouroids (n=14 mice) were established from APCΔhep and βcatΔex3 mouse models, which are clinically relevant models for β-catenin-activated HCC and mesenchymal HB. We developed a new methodological approach based on dynamic suspension culture in a rotating bioreactor. Morphological and molecular characteristics, as well as drug responses were evaluated by histology, immunohistochemistry, immunofluorescence, transcriptomics and RT-qPCR. This easy-to-implement methodology allows for the rapid production of large numbers of uniform organoids and tumouroids (30-75 per tumour) with no detectable cell death and hypoxia in their core. The robustness of the approach is also illustrated by the preservation of histological architecture, cell diversity (tumour cells, macrophages, endothelial cells) and gene expression in organoids and tumouroids compared with native liver tissue. Gene set enrichment analysis showed significant enrichment of 10 human HCC/HB tumour signatures in murine tumouroids. Organoids and tumouroids showed expected responsiveness to specific inhibitors, including the β-catenin antagonist WNTinib. These organoids and tumouroids represent robust in vitro models of β-catenin-driven HCC and mesenchymal HB. They provide a scalable platform for drug screening and may support the development of "à la carte" therapies urgently needed for these indications. Impact and implications; This study addresses the need for representative in vitro models to investigate β-catenin-driven liver cancers. The tumouroids developed here provide robust and reproducible 3D models that closely recapitulate the histological features, cellular diversity, and gene expression profiles of native liver tumours. These models offer a valuable platform for studying tumour biology, evaluating therapeutic candidates, and supporting the development of personalized treatment strategies. They may also contribute to reducing the use of animals in preclinical research.
2026-09-15 | Tumor Topography Remodels TME Signalling via Compartment-Specific Host-Microbiome-Tumor Crosstalk in Hepatoblastoma.
Background & Aims: Signaling within the tumor microenvironment (TME) emerges from dynamic crosstalk among cancer cells, host tissues, and the microbiome. Orthotopic and ectopic xenograft models are widely used in preclinical liver cancer research, yet it remains unclear to what extent tumor location shapes systemic host responses and gut-liver communication. We therefore investigated how anatomical context influences host transcriptomes and spatially resolved intestinal microbial ecosystems in hepatoblastoma (HB). Methods: We integrated bacterial/archaeal ecology with host and xenograft transcriptomes in orthotopic versus ectopic hepatoblastoma xenografts in male athymic CAnN.Cg-Foxn1nu/Crl mice. Single-sample GSEA, sparsity-aware networks, and DIABLO multi-block integration mapped pathway-level coordination across intestinal segments, stool, secondary lymphoid organs, livers, and tumors. Results: Tumor localization was associated with compartment-specific differences in host signaling, with the mesenteric lymph node and liver showing prominent shifts in TNFA/NF-κB, hypoxia, unfolded protein response, xenobiotic metabolism, mTORC1, KRAS, epithelial-mesenchymal transition, and MYC/E2F cell-cycle axes. Archaea exhibited pronounced, niche-specific signatures that showed positive correlations with proliferative and inflammatory Hallmarks and negative correlations with interferon pathways. Multi-omics integration (r ≥ 0.85) indicated coordinated variation linking specific microbial families to host and tumor programs and positioned the xenograft block as a hub connecting EMT, mTORC1, and angiogenesis to defined archaeal and bacterial taxa. Conclusions: Tumor topography remodels TME signaling through compartment-dependent host-microbiome-tumor crosstalk, with archaeal domains emerging as salient correlates of proliferative and stress-response networks. These findings provide a systems framework and testable hypotheses for therapeutic modulation of TME signaling via interkingdom interactions.
2026-08-27 | Treatment Adaptation to Surgical Timing in Pediatric Hepatoblastoma: A 19-Year Single-Center Experience With Resection and Liver Transplantation.
The management of hepatoblastoma (HB) relies on chemotherapy combined with surgery, either liver resection (LR) or liver transplantation (LT), with reported overall survival (OS) of 80%, cardiac toxicity of 6%, nephrotoxicity of 21%, ototoxicity of 32%-46%. In clinical practice, deviations from protocol-defined chemotherapy are often required to achieve resectability or bridge to transplantation. We aimed to evaluate the impact of treatment adaptation to surgical timing on OS and toxicity in a selected group of patients referred to a transplantation center. We retrospectively analyzed patients with HB treated according to SIOPEL protocols at our center between 2004 and 2022. We collected clinical data, focusing on deviations from protocol-specified therapy, timing of medical and surgical treatment, OS, treatment-related toxicities (left ventricular ejection fraction, LVEF< 50%, estimated glomerular filtration rate, eGFR< 90 mL/mL/m2, increased hearing threshold of 20-40 dB at 4 kHz). Forty-two patients, median age at diagnosis 1.9 years (IQR 0.7-3.5), 16/42 (38.1%) with metastatic disease, 24/42 (57.1%) with vascular involvement were recorded. Additional chemotherapy beyond protocol indications, due to persistent pulmonary metastases, delayed organ availability, or disease progression was administered to 17/20 (85%) who underwent first-line LT and 10/22 (45%) who underwent LR (p = 0.007). Death occurred in 3/20 (15%) versus 7/22 (31.8%) (p = 0.2) respectively. After median follow-up of 4.5 years (IQR 1.2-6.2) OS is 32/42 (71.4%); cardiotoxicity developed in 1/42 (2.4%), nephrotoxicity in 8/42 (19%), ototoxicity in 9/42 (21.4%). A large proportion of patients with HB require adaptation of protocol-specified therapy, especially LT candidates. This favors successful management and is not associated with increased toxicity compared to previous reports.
2026-08-14 | Antimicrobial, anti-biofilm, and anticancer activities of green-synthesized silver nanoparticles using Crossostephium chinense (L.) Makino aqueous leaf extract.
The increasing burden of infectious diseases, driven by microbial pathogenicity and antimicrobial resistance, necessitates the development of effective and sustainable antimicrobial strategies. In that context, this study reports, for the first time, the green synthesis of silver nanoparticles (AgNPs) using an aqueous extract of Crossostephium chinense (L.) Makino (CC) leaves, wherein plant-derived phytochemicals act as natural reducing and capping agents. Mass spectrometric analyses of CC aqueous leaf extract identified 62 possible metabolites, including flavonoids, phenolics, and terpenoids, that possibly facilitate nanoparticle synthesis. The synthesized C. chinense-derived silver nanoparticles (CC-AgNPs) were characterized as moderately stable, crystalline, spherical with sizes ranging from 20-80 nm. CC-AgNPs displayed broad-spectrum antimicrobial activity, showing the greatest susceptibility in Bacillus subtilis and Pseudomonas aeruginosa, with a minimum inhibitory concentration (MIC) of 6 μg/mL, while electron microscopy confirmed severe structural damage to bacterial membranes. Furthermore, CC-AgNPs displayed strong antibiofilm activity, achieving up to 92% biofilm inhibition in B. subtilis at 12 μg/mL. The anticancer potential of CC-AgNPs was evaluated against breast cancer (MCF-7 and MDA-MB-231), chronic myelogenous leukemia (K562), and hepatoblastoma (HepG2) cell lines. Among these, MDA-MB-231 cells were the most sensitive, exhibiting the lowest IC50 value. Further mechanistic investigations in MDA-MB-231 cells demonstrated apoptosis induction, as evidenced by nuclear fragmentation, Annexin V/PI staining and activation of caspases. In conclusion, these findings highlight CC-AgNPs as promising candidates for antimicrobial, antibiofilm, and anticancer applications.
2026-08-13 | [Efficacy comparisons of chemotherapy regimens with different intensities in high-risk pediatric hepatoblastoma].
Objective: To evaluate the efficacy of different chemotherapy regimens in children with high-risk hepatoblastoma (HB). Methods: A retrospective cohort study was conducted on 99 patients under 18 years old with high-risk HB treated at Sun Yat-sen University Cancer Center between December 2004 and July 2024. The patients were divided into three groups: the PLADO regimen (cisplatin in combination with doxorubicin, n=27), the C5VD/IIV regimen (alternating cycles of cisplatin/5-flourouracil/vincristine/doxorubicin with irinotecan/ifosfamide/vincristine, n=29), and the modified SIOPEL-4 regimen (the original SIOPEL-4 regimen with omitted high-dose cisplatin on day15, n=43). Short-term efficacy, adverse effects, and long-term survival were compared among the three groups. Results: The objective response rates for the PLADO, C5VD/IIV, and modified SIOPEL-4 groups were 73.9% (17/23), 70.8% (17/24), and 88.6% (31/35), respectively, with no statistically significant difference among the three groups (P=0.190). The disease control rates were 82.6% (19/23), 83.3% (20/24), and 100.0% (35/35), the 3-year progression-free survival (PFS) rates were 19.2%, 37.0%, and 56.7%, and the 3-year overall survival (OS) rates were 69.2%, 55.6%, and 79.0%, respectively. The modified SIOPEL-4 group showed significantly better disease control rate and PFS rate compared withthe other two groups (both P＜0.05). After merging the PLADO and C5VD/IIV groups, the modified SIOPEL-4 group demonstrated significantly superior PFS and OS rates (both P＜0.05). Conclusions: The efficacy of modified SIOPEL-4 regimen in treating high-risk HB is superior compared with those of PLADO and C5VD/IIV regimens, but there remains room for further improvement in efficacy. Intensifying supportive care and pursuing aggressive local therapies, especially upfront liver transplantation for locally inoperable tumors, may further improve outcomes.
proteins
2026-04-06 | Overexpression of ONECUT1 suppresses hepatoblastoma progression via modulating tumor cell growth and tumor microenvironment.
Hepatoblastoma is the most common malignant liver tumor in children. Our previous work showed that enforced expression of the transcription factor One Cut Homeobox 1 (ONECUT1) suppresses the initiation of hepatoblastoma. However, it remains unclear whether increasing ONECUT1 expression can also inhibit tumor progression after tumors have already formed. The purpose of this study was to determine the effects of ONECUT1 induction on tumor cell behavior and tumor growth during established hepatoblastoma progression. We generated doxycycline-inducible expression systems to upregulate ONECUT1 in hepatoblastoma cells in culture and in mouse models. In human hepatoblastoma cells, induction of ONECUT1 promoted apoptotic cell death and reduced cell cycle progression. In a subcutaneous xenograft model using immunodeficient mice, ONECUT1 induction slowed tumor growth but did not cause tumor regression. We then established an orthotopic HB model in FVB/N mice by tail-vein injection of YAP/β-catenin/TRE-ONECUT1 plasmids. ONECUT1 expression in existing mouse HB cells was induced by feeding the mice with DOX-water. Remarkably, tumor regression was observed following ONECUT1 induction. Histological analyses showed extensive necrosis and apoptosis in tumor lesions following induction of ONECUT1, accompanied by robust macrophage infiltration and moderate T cell infiltration. Depletion of T cells using antibodies against CD4 and CD8 weakened the antitumor effect of ONECUT1, indicating that T-cell activity contributes to tumor suppression. Transcriptomic analysis further suggested that ONECUT1 may promote antitumor immune responses in part by increasing expression of immune-related cytokines. Induction of ONECUT1 suppresses hepatoblastoma progression by inhibiting tumor cell growth and by reshaping the tumor immune microenvironment. These findings reveal a previously unrecognized antitumor role of ONECUT1 during hepatoblastoma progression and suggest that restoring ONECUT1 activity may represent a promising therapeutic strategy for this pediatric malignancy.
2026-01-05 | Disrupting the Formation of YAP Condensates Promotes the Activation of AMPKα to Inhibit the Progression of Primary Liver Cancer.
Liquid-liquid phase separation, a process facilitating biomolecular condensate formation, plays a critical role in various pathologies, including tumorigenesis, metabolic disorders, and neurodegenerative diseases. Dysregulated phase separation has been linked to tumor initiation and progression. However, the pathological significance of phase separation in primary tumors of mice remains largely unexplored. We constructed a series of primary liver cancer models via hydrodynamic tail vein injection and confirmed that endogenous Yes-associated protein (YAP) formed numerous condensates in primary liver cancer of mice. Deletion, mutagenesis, and replacement assays confirmed that the formation of YAP condensates plays a critical role in the development of cellular myelocytomatosis oncogene (c-Myc)-induced hepatocellular carcinoma, myristoylated AKT (myr-AKT)-induced intrahepatic cholangiocarcinoma, and amino-terminal missing first 90 amino acids of catenin beta 1 (ΔN90-CTNNB1)-induced hepatoblastoma. We found that the YAP phase separation inhibits the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, thereby promoting the occurrence and development of primary liver cancer. Additionally, we identified that the TEA domain transcription factor 1 (TEAD1)-derived peptide effectively disrupted YAP condensate formation, leading to AMPKα activation in vivo and inhibition of primary liver cancer progression. This study systematically confirms that YAP phase separation plays a crucial role in the progression of various primary liver cancers and further substantiates that strategic disruption of these condensates constitutes an effective treatment for primary liver cancer in vivo.
2024-12-06 | Single-Cell RNA Sequencing Reveals LEF1-Driven Wnt Pathway Activation as a Shared Oncogenic Program in Hepatoblastoma and Medulloblastoma
(1) Background: Hepatoblastoma and medulloblastoma are two types of pediatric tumors with embryonic origins. Both tumor types can exhibit genetic alterations that affect beta-catenin and Wnt pathway; (2) Materials and Methods: This study used bioinformatics and integrative analysis of multi-omics data at both the tumor and single-cell levels to investigate these two distinct pediatric tumors: medulloblastoma and hepatoblastoma; (3) Results: Cross-transcriptome analysis revealed a commonly regulated expression signature between hepatoblastoma and medulloblastoma tumors. Among the commonly upregulated genes, the transcription factor LEF1 was significantly expressed in both tumor types. In medulloblastoma, LEF1 upregulation is associated with the WNT-subtype. Analysis of LEF1 genome binding occupancy in H1 embryonic stem cells identified 141 LEF1 proximal targets activated in WNT-medulloblastoma, 13 of which are involved in Wnt pathway regulation: RNF43, LEF1, NKD1, AXIN2, DKK4, DKK1, LGR6, FGFR2, NXN, TCF7L1, STK3, YAP1, and NFATC4. An expression score based on these 13 WNT-LEF1 targets accurately predicted the WNT-subtype in two independent medulloblastoma transcriptome cohorts. At the single-cell level, the WNT-LEF1 expression score was exclusively positive in WNT-medulloblastoma tumor cells. This WNT-LEF1-dependent signature was also confirmed as activated in the hepatoblastoma tumor transcriptome. At the single-cell level, the WNT-LEF1 expression score was higher in tumor cells from both human hepatoblastoma samples and a hepatoblastoma patient-derived xenotransplant model; (4) Discussion: This study uncovered a shared transcriptional activation of a LEF1-dependent embryonic program, which orchestrates the regulation of the Wnt signaling pathway in tumor cells from both hepatoblastoma and medulloblastoma.
2024-10-03 | Gas1-Mediated Suppression of Hepatoblastoma Tumorigenesis
Background and Aims: Hepatoblastoma (HB), the most common pediatric liver cancer, often dysregulates the Wnt/β-catenin, Hippo and NFE2L2/NRF2 pathways. Pairwise combinations of oncogenically active forms of the terminal transcription factor effectors of these pathways, namely β-catenin (B), YAP (Y) and NRF2 (N) generate HBs in mice, with the triple combination (B+Y+N) being particularly potent. Each tumor group alters the expression of thousands of B-,Y- and N-driven unique and common target genes. Identifying those most responsible for transformation is thus an important question as it might reveal new mechanistic insights and therapeutic opportunities. Approach and Results: Transcriptional profiling of >60 murine HBs driven by the above oncogenic combinations and different B mutants and in genetic backgrounds that impair tumor growth rates but not initiation has revealed a common set of 22 "BYN genes" that are similarly deregulated in all cases. Many are associated with multiple "Cancer Hallmarks" and their expression levels often correlate with survival in human HBs, hepatocellular carcinomas and other cancers. Among the most down-regulated of these is Gas1, which encodes a Glycosylphosphatidylinositol (GPI)-linked outer membrane protein. We show here that restoring Gas1 expression impairs B+Y+N-driven HB tumor growth in vivo and in HB-derived immortalized cell lines in vitro in a manner than requires membrane anchoring of the protein via its GPI moiety. Conclusions: Our findings implicate Gas1 as a proximal mediator of HB pathogenesis and validate the BYN gene set as one deserving of closer additional scrutiny in future studies.
2024-09-05 | Abstract B024: Single cell transcriptomics and patient-derived tumoroids reveal that hepatobiliary lineage programs cooperate with Wnt pathway mutations to drive cell proliferation in hepatoblastoma
Abstract Cancers evolve not only through the acquisition and clonal transmission of somatic mutations but also by non-genetic mechanisms that modify cell phenotype. Such epigenetic causes of intra-tumoral heterogeneity may be particularly important in pediatric cancers with low rates of genomic mutations. Hepatoblastoma, the most common primary liver malignancy in children, has one of the lowest mutational burdens of all cancers, providing an ideal system to elucidate non-genetic mechanisms of intra-tumoral heterogeneity. Up to 80-90% of hepatoblastomas have activating mutations in CTNNB1 and the Wnt pathway. Yet, despite their simple genomics, these tumors exhibit significant histologic heterogeneity, including epithelial (embryonal and fetal histology) and mesenchymal components. Using transcriptomics and patient-derived tumoroids, we find that hepatobiliary lineage programs modulate the transcriptional outcome of mutated CTNNB1. A subset of cholangiocytic-like tumor cells express the growth factor FGF19, which promotes proliferation of neighboring cells in conjunction with activated Wnt signaling. To characterize the transcriptional profiles of the distinct histologic components of hepatoblastoma, we used laser capture microdissection to isolate tumor regions identified as embryonal, fetal, or mesenchymal histology, as well as adjacent normal liver. While all tumor regions showed increased expression of Wnt target genes as compared to normal liver, the embryonal components showed even higher expression of Wnt target genes as compared to the fetal components, as well as increased proliferation markers and higher expression of the embryonic biliary transcription factor SOX4. RNA in situ hybridization in primary hepatoblastomas revealed distinctive foci of embryonal hepatoblastoma cells that express the growth factor FGF19. These FGF19-expressing cells were surrounded by FGF19-negative cells that expressed KLB, the co-receptor for FGF19 signaling, and showed an increased proliferation. We therefore hypothesized that FGF19 acts in a paracrine fashion to drive cell cycle progression of hepatoblastoma cells in cooperation with constitutively active Wnt signaling. We further generated patient-derived tumoroids to systematically test the requirements for exogenous growth factors. We found that despite activated Wnt signaling, FGF19-negative tumor cells required additional exogenous growth factors to proliferate. In some tumoroids, subsets of cells expressed FGF19 endogenously, downstream of Wnt/beta-catenin and SOX4, acting as a paracrine signal. We conclude that the embryonic biliary transcription factor SOX4 cooperates with mutated beta-catenin, inducing FGF19 as a paracrine growth signal that can promote proliferation of FGF19-negative tumor cells. Thus, in this pediatric cancer presumed to originate from a multipotent hepatobiliary progenitor, lineage-driven heterogeneity results in a functional growth advantage, a non-genetic mechanism whereby developmental lineage programs influence tumor evolution, with implications for treatment. Citation Format: Peng V. Wu, Matt Fish, Florette K. Hazard, Chunfang Zhu, Sujay Vennam, Hannah Walton, Joanna Przybyl, Maurizio Morri, Norma Neff, Robert B. West, Roel Nusse. Single cell transcriptomics and patient-derived tumoroids reveal that hepatobiliary lineage programs cooperate with Wnt pathway mutations to drive cell proliferation in hepatoblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B024.
oligonucleotides
2026-09-10 | A 177Lu-Labeled Circular Bivalent Aptamer for PTK7-Targeting Radionuclide Therapy in Ovarian Cancer and Orthotopic Hepatoblastoma.
Targeted radionuclide therapy (TRT) is a promising strategy for precision oncology but is limited by the lack of high-performance targeting ligands. Here, we report a lutetium-177 (177Lu)-labeled PTK7-targeted cyclized bivalent aptamer (CBSgc8) for treating an orthotopic hepatoblastoma. The cyclized multivalent design enhances biostability and binding affinity, while 177Lu labeling preserves its functional properties. The resulting 177Lu-CBSgc8 exhibited high serum stability, strong specificity for PTK7-positive cells, efficient internalization, and dose-dependent cytotoxicity in vitro. In vivo, 177Lu-CBSgc8 inhibited tumor growth in an OVCAR3 ovarian cancer model, although tumor accumulation remained limited. Given its PTK7-targeting capability and preferential hepatic distribution, we further evaluated its therapeutic potential in an orthotopic HepG2 hepatoblastoma model. In this setting, 177Lu-CBSgc8 achieved 76.6% tumor growth inhibition with a favorable safety. These findings demonstrate the potential of exploiting tissue distribution characteristics together with molecular targeting to expand the applicability of aptamer-based TRTs.
2025-05-03 | Identification of a Growth-Promoting Gene Cluster in the Region 2q24 as a Driver of Tumorigenesis in Childhood Hepatoblastoma.
Hepatoblastoma (HB) represents the most common primary malignancy of the liver in childhood. Cytogenetic studies uncovered characteristic copy number alterations in HB. The frequent gain of chromosome 2q and particularly the recurrent 2q24 amplification suggest the presence of a so far unidentified oncogenic driver within this amplicon. Herein, high-resolution copy number profiles from 76 patients with HB were generated by using molecular inversion probe array technology. 2q gain was present in 63.2%, and 2q24 high-gain/amplification was present in 14.5% of patients analyzed. In the smallest overlapping region at 2q24.2q24.3, spanning >5.2 Mbp, 22 protein-coding genes, 2 long noncoding RNA genes, and one miRNA gene were mapped. RNA expression analysis of these smallest overlapping region genes identified RBMS1, BAZ2B, MARCH7, DPP4, FIGN, and TANK as overexpressed in 2q24 high-gain/amplified HB cases. Accordingly, these six genes were selected for further investigation. In situ, immunohistochemical staining showed higher protein expression of these genes in 2q24 high-gain HB tissue sections. In vitro, functional analyses were performed in established human HB cell lines carrying a 2q (high-)gain. Knockdown of these genes by specific siRNAs resulted in reduced proliferation and marked reduction of Wnt pathway activity. These genes located within the 2q24 amplicon might collaborate in driving cellular growth by interaction with the Wnt pathway that is known to be activated pathologically in HB.
2024-09-09 | N6-methyladenosine modification of LATS2 promotes hepatoblastoma progression by inhibiting ferroptosis through the YAP1/ATF4/PSAT1 axis.
Ferroptosis has attracted extensive interest from cancer researchers due to its substantial potential as a therapeutic target. The role of LATS2, a core component of the Hippo pathway cascade, in ferroptosis initiation in hepatoblastoma (HB) has not yet been investigated. Furthermore, the underlying mechanism of decreased LATS2 expression remains largely unknown. In the present study, we demonstrated decreased LATS2 expression in HB and that LATS2 overexpression inhibits HB cell proliferation by inducing ferroptosis. Increased LATS2 expression reduced glycine and cysteine concentrations via the ATF4/PSAT1 axis. Physical binding between YAP1/ATF4 and the PSAT1 promoter was confirmed through ChIP‒qPCR. Moreover, METTL3 was identified as the writer of the LATS2 mRNA m6A modification at a specific site in the 5' UTR. Subsequently, YTHDF2 recognizes the m6A modification site and recruits the CCR4-NOT complex, leading to its degradation by mRNA deadenylation. In summary, N6-methyladenosine modification of LATS2 facilitates its degradation. Reduced LATS2 expression promotes hepatoblastoma progression by inhibiting ferroptosis through the YAP1/ATF4/PSAT1 axis. Targeting LATS2 is a potential strategy for HB therapy.
2024-08-07 | From diagnosis to therapy: The critical role of lncRNAs in hepatoblastoma.
According to findings, long non-coding RNAs (lncRNAs) serves an integral part in growth and development of a variety of human malignancies, including Hepatoblastoma (HB). HB is a rare kind of carcinoma of the liver that mostly affects kids and babies under the age of three. Its manifestations include digestive swelling, abdominal discomfort, and losing weight. This thorough investigation digs into the many roles that lncRNAs serve in HB, giving views into their varied activities as well as possible therapeutic consequences. The function of lncRNAs in HB cell proliferation, apoptosis, migratory and penetrating capacities, epithelial-mesenchymal transition, and therapy tolerance is discussed. Various lncRNA regulatory roles are investigated in depth, yielding information on their effect on essential cell processes such as angiogenesis, apoptosis, immunity, and growth. Circulating lncRNAs are currently acknowledged as potential indications for the initial stages of identification of cancer, with the ability to diagnose as well as forecast. In addition to their diagnostic utility, lncRNAs provide curative opportunities as locations and actors, contributing to the expanding landscape of cancer research. Several HB-linked lncRNAs have been demonstrated to exhibit abnormal expression and are involved in tumor-like characteristics via DNA, RNA, or protein binding or encoding short peptides. As a result, a better knowledge of lncRNA instability might bring fresh perspectives into HB etiology as well as innovative strategies for HB early diagnosis and therapy. We describe the abnormalities of lncRNA expression in HB and their tumor-suppressive or carcinogenic activities during HB carcinogenesis in this study. Furthermore, we explore lncRNAs' diagnostic and therapeutic possibilities in HB.
2024-06-12 | MicroRNA-141-regulated KLK10 and TNFSF-15 gene expression in hepatoblastoma cells as a novel mechanism in liver carcinogenesis.
Liver cancer is one of the most pivotal global health problems, leading hepatocellular carcinoma (HCC) with a significant increase in cases worldwide. The role of non-coding-RNA in cancer proliferation and carcinogenesis has attracted much attention in the last decade; however, microRNAs (miRNAs), as non-coding RNA, are considered master mediators in various cancer progressions. Yet the role of miR-141 as a modulator for specific cellular processes in liver cancer cell proliferation is still unclear. This study identified the role of miR-141 and its potential functions in liver carcinogenesis. The level of miR-141 in HepG2 and HuH7 cells was assessed using quantitative real-time PCR (qRT-PCR) and compared with its expression in normal hepatocytes. A new miR-141 construct has been performed in a CMV promoter vector tagged with GFP. Using microarray analysis, we identified the potentially regulated genes by miR-141 in transfected HepG2 cells. The protein profile of the kallikrein-related peptidase 10 (KLK10) and tumor necrosis factor TNFSF-15 was investigated in HepG2 cells transfected with either an inhibitor, antagonist miR-141, or miR-141 overexpression vector using immunoblotting and flow cytometry assay. Finally, ELISA assay has been used to monitor the produced inflammatory cytokines from transfected HepG2 cells. Our findings showed that the expression of miR-141 significantly increased in HepG2 and HuH7 cells compared to the normal hepatocytes. Transfection of HepG2 cells with an inhibitor, antagonist miR-141, showed a significant reduction of HepG2 cell viability, unlike the transfection of miR-141 overexpression vector. The microarray data of HepG2 cells overexpressed miR-141 provided a hundred downregulated genes, including KLK10 and TNFSF-15. Furthermore, the expression profile of KLK10 and TNFSF-15 markedly depleted in HepG2 cells transfected with miR-141 overexpression accompanied by a decreasing level of interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α), indicating the role of miR-141 in HepG2 cell proliferation and programmed cell death. Interestingly, the experimental rats with liver cancer induced by Diethylnitrosamine injection further confirmed the upregulation of miR-141 level, IL-10, and TNF-α and the disturbance in KLK10 and TNFSF-15 gene expression compared with their expression in normal rats. The in-silico online tools, IntaRNA and miRWalk were used to confirm the direct interaction and potential binding sites between miR-141 and identified genes. Thus, the seeding regions of potential targeted sequences was cloned upstream of luciferase reporter gene in pGL3 control vector. Interestingly, the luciferase activities of constructed vectors were significantly decreased in HepG2 cells pre-transfected with miR-141 overexpression vector, while increasing in cells pre-transfected with miR-141 specific inhibitor. In summary, these data suggest the crucial role of miR-141 in liver cancer development via targeting KLK10 and TNFSF-15 and provide miR-141 as an attractive candidate in liver cancer treatment and protection.
cell therapies
2026-09-09 | Complete Regression of Hepatoblastoma after Interleukin-15– and Interleukin-21–Coexpressing CAR T-Cell Therapy
A 3-year-old boy with chemotherapy-resistant metastatic hepatoblastoma had complete regression lasting at least 12 months after two infusions of glypican-3–specific CAR T cells coexpressing interleukin-15 and interleukin-21.
2026-06-27 | T-cell receptor-engineered T-cell therapy using a glypican-3-specific TCR derived from a hepatoblastoma vaccine responder for HLA-A2-positive glypican-3-expressing cancers.
Glypican-3 (GPC3) is highly expressed in most hepatocellular carcinomas (HCCs) and hepatoblastoma, shows minimal expression in non-tumor adult tissues, and is also detected in several other malignancies, making it an ideal target for anticancer immunotherapy. We previously demonstrated in clinical trials that GPC3 peptide vaccination can induce durable antitumor immunity in patients with HCC and pediatric hepatoblastoma and established human leukocyte antigen (HLA)-A∗02:01-restricted GPC3-specific cytotoxic T lymphocyte (CTL) clones. In this study, we isolated high-avidity T-cell receptors (TCRs) from CTL clones established from a pediatric hepatoblastoma patient who achieved long-term recurrence-free survival for more than 10 years after surgical resection of pulmonary metastases followed by GPC3 peptide vaccination. Using a retroviral vector incorporating endogenous TCR suppression, these TCR genes were introduced into primary human T cells to generate GPC3-specific TCR-engineered T cells (TCR-T cells). These TCR-T cells exhibited GPC3-specific recognition and significant cytotoxicity against GPC3-positive tumor cells in vitro, while showing minimal activity against GPC3-negative targets. Moreover, GPC3-specific TCR-T cells migrated to tumor sites, resulting in the prevention of tumor engraftment as well as tumor growth suppression and stabilization in xenograft models. GPC3-targeted TCR-T cells derived from CTLs induced by GPC3 peptide vaccination demonstrated potent antitumor activity against HLA-A∗02-positive and GPC3-positive cancers. These findings provide an important rationale for Phase I clinical trials of GPC3-targeted TCR-T cells as a promising therapeutic strategy for GPC3-expressing solid tumors, including HCC and refractory hepatoblastoma.
2026-06-01 | Excellent Outcomes With High-Risk Pediatric Hepatoblastoma: A Detailed Analysis of a Large, Single-Center Experience.
Hepatoblastoma (HBA) is a rare pediatric malignancy treatable with liver transplantation (LTx). Limited data exist on outcomes after LTx for HBA. This study evaluates the therapeutic efficacy of LTx in pediatric patients with HBA, delineates principal complications, and assesses long-term psychosocial outcomes. This retrospective cohort study analyzed a prospectively maintained database of children undergoing LTx for HBA at a single US center from 1984 to 2025. Primary outcomes were patient and graft survival at 1, 5, and 10 years post-LTx and HBA recurrence. Secondary outcomes included post-LTx complications, recurrence predictors, and psychosocial parameters. Of 55 patients (60% female; 40% Hispanic; mean age at diagnosis, 36 months), most had PRETEXT stage III (44%) or IV (47%) disease; mean α-fetoprotein level at diagnosis was 569 355 ng/mL. All but 1 received chemotherapy; 15 (27%) had pre-LTx resection. Mean wait time to LTx was 10 months. Pre-LTx metastatic disease (pulmonary) was present in 5 patients (9%). Explant pathology showed macrovascular invasion (n = 16), positive lymph nodes (n = 3), and extra-hepatic tumor invasion/rupture (n = 2). Post-LTx complications included HBA recurrence (20%), hepatic artery thrombosis (11%), and biliary stricture (20%). Patient survival was 89% at 1 year, 74% at 5 and 10 years; graft survival was 89%, 73%, and 73%, respectively. Significant predictors of recurrence were older age at LTx (p = 0.01), longer waiting time to LTx (p = 0.02), prior resection (p = 0.01), larger tumor size (p = 0.03), vascular invasion (p = 0.02), and utilization of a segmental graft (p = 0.002). Mortality was mainly due to recurrence. Psychosocially, 14 patients needed special education, 10 had developmental delays, 5 of 12 adults completed high school, 2 earned college degrees, and 3 are employed. This large single-center study demonstrates favorable survival after LTx for high-risk HBA. Recurrence predictors support avoiding pre-LTx resection in high-risk cases. While living donor or split grafts can expedite transplantation, segmental grafts were independently linked to higher recurrence. Notably, metastases at diagnosis did not increase recurrence, supporting aggressive treatment. The rate of HAT and biliary stricture was significantly higher for children transplanted for HBA than for our overall pediatric experience. These findings help guide the management of this rare malignancy.
2025-12-04 | Identification of CD7 as a novel biomarker of embryonal hepatoblastoma.
This study aimed to investigate the expression of cluster of differentiation 7 (CD7) in hepatoblastoma (HB) and its potential use as a novel biomarker of HB. CD7 expression was investigated in human HB samples at the gene level by bulk, single-cell RNA sequencing, and spatial transcriptomic analyses, in addition to the protein level by immunohistochemical (IHC) staining. CD7 gene expression-based survival analysis was also conducted, along with gene set enrichment analysis (GSEA) of the CD7-SECTM1 receptor-ligand gene pair. CD7 was differentially expressed in human HB at both the gene level by various bioinformatics analyses, and the protein level by IHC, with remarkably higher expression levels in embryonal HB. Conversely, CD7 was not expressed in other primary adult liver tumors. CD7high HB cases showed poorer 5-year event-free survival (P = 0.016), and GSEA demonstrated that CD7 is linked to the embryonal MYCN transcription factor, as were protumor kinases such as JAK3, and marginally MAPK14 and MAPK3. CD7 is expressed in human HB, especially the embryonal histological subtype, and appears to be linked to tumor progression and poor clinical outcomes. Nevertheless, CD7-targeted chimeric antigen receptor T cells could be proposed as a promising immunotherapy for embryonal HB.
2025-10-11 | Claudin 6 is a suitable target for CAR T-cell therapy in atypical teratoid/rhabdoid brain tumors and other pediatric solid tumors.
Solid tumors comprise approximately 60% of all pediatric cancers. Relapsed or refractory tumors of the central nervous system (CNS), such as atypical teratoid/rhabdoid tumors (AT/RTs), are the leading cause of death in children with cancer. Claudin 6 (CLDN6)-specific chimeric antigen receptor (CAR) T cells have demonstrated activity in preclinical and clinical studies in various solid adult cancers. However, the suitability of CLDN6 as a target in pediatric tumors and their susceptibility to CAR T-cell therapy has yet to be established. This study aimed to evaluate the suitability of CLDN6 as a target for CAR T-cell therapy of pediatric solid tumors. Immunohistochemical CLDN6 expression was assessed in fetal normal tissues (n=91), pediatric normal tissues (n=157), and two sets of pediatric tumor tissues (n=527 and n=49) using a combined score that includes the percentage of stained cells with a 4-point intensity scale (0 to 3+). The antitumor activity of CLDN6 RNA-transduced CAR T cells against AT/RT cell lines was assessed with in vitro assays and in immunodeficient NOD-SCID-γc-/- (NSG) mouse models bearing orthotopic xenograft tumors. Membranous CLDN6 expression, as detected by immunohistochemistry, was widely observed in fetal tissues but was absent in almost all non-malignant pediatric tissues, except for very rare, scattered cells with 1+ to 2+ intensity in kidney, pancreas, pituitary, and salivary gland tissues. Membranous CLDN6 expression was frequently detected in a subset of the pediatric tumor entities, including germ cell tumors (93% of samples with CLDN6-positive cells), nephroblastoma (64%), extracranial malignant rhabdoid tumors (50%), and AT/RTs (39%). In CLDN6-positive samples, CLDN6 was generally expressed with 2+ or 3+ intensity in substantial proportions of the cancer cells. Strong CLDN6 expression was also detected in single samples of hepatoblastoma, Ewing sarcoma/other embryonal tumors, and osteosarcoma.In experimental models, CLDN6-CAR T cells led to antigen-specific killing of endogenously CLDN6-expressing AT/RT cell lines in vitro and exhibited potent and specific antitumor activity in mice bearing orthotopic CLDN6-expressing AT/RT xenograft tumors. These results support CLDN6 as an oncofetal cell-surface antigen that may be suitable for CAR T-cell targeting in pediatric solid tumors, including those of the CNS.
other
2026-06-11 | Macrophage Polarization and Spatial Architecture Characterize the Tumor Immune Microenvironment and Prognosis in Hepatoblastoma.
Hepatoblastoma, the most common primary pediatric liver malignancy, exhibits resistance to contemporary treatments in a subset of patients. Understanding the tumor immune microenvironment is essential for the development of novel immuno-oncological therapies. Herein, the microenvironment of hepatoblastoma was characterized by mapping the spatial distribution of immune cells, identifying prognostic immune features, assessing chemotherapy-induced alterations, and exploring potential immunotherapeutic targets. Whole-slide multiplex immunofluorescence staining (n = 35) was performed on formalin-fixed, paraffin-embedded hepatoblastoma specimens from 25 patients. Immune cell densities were analyzed in precytotoxic and post-cytotoxic treatment samples. Spatial characteristics were assessed using nearest-neighbor distances and Gcross functions, and differential protein abundance patterns were identified using quantitative proteomics (n = 18). This study revealed a predominantly myeloid-rich microenvironment in hepatoblastoma. Macrophages shifted toward a proinflammatory state following cytotoxic treatment. Proinflammatory phosphorylated STAT1 (pSTAT1)+ macrophages were associated with improved patient survival when retained in proximity to tumor cells after chemotherapy. Down-regulation of extracellular matrix pathways was observed in these pSTAT1-rich samples. Common lymphatic endothelial and vascular endothelial receptor 1 (CLEVER-1), an immunosuppressive marker and potential therapeutic target, was abundantly expressed, particularly in stromal macrophages. This study highlights the significance of macrophage phenotypes in hepatoblastoma and their potential as a therapeutic target. Moreover, the findings underline the prognostic value of pSTAT1+ macrophages and CLEVER-1 as a promising immunotherapy target. Future research should explore combination strategies to exploit chemotherapy-induced shifts in macrophage polarization.
2026-04-06 | PRECLINICAL ACTIVITY OF THE B7-H3- TARGETING ANTIBODY-DRUG CONJUGATE (ADC) VOBRAMITAMAB DUOCARMAZINE (VOBRA DUO) IN PEDIATRIC SOLID TUMORS.
Vobramitamab duocarmazine (vobra-duo) is a duocarmycin-based, humanized antibody-drug conjugate (ADC) targeting B7-H3, with a drug-to-antibody ratio of ~2.7. Vobra-duo has demonstrated robust antitumor activity in multiple adult cancer models, along with favorable pharmacokinetic and safety profiles in cynomolgus monkeys. Early results from phase I/II clinical trials (NCT03729596) have shown manageable toxicity and promising objective responses in patients with metastatic castration-resistant prostate cancer. Given the high expression of B7-H3 in pediatric solid tumors, this target is emerging as a compelling therapeutic opportunity in pediatric oncology. Antitumor activity of vobra-duo was evaluated in pediatric solid tumor xenograft models, including Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, osteosarcoma, malignant rhabdoid tumor, hepatoblastoma, and Wilms tumor. Tumor-bearing mice received a single intraperitoneal dose of vobra-duo (6 mg/kg) or a matched control ADC (SYD988, anti-CD20 ADC with identical linker and payload). Tumor progression was defined as a fourfold increase in tumor volume. Event-free survival was analyzed using Kaplan-Meier methods, and responses were categorized as partial, complete, or maintained complete response. Vobra-duo induced objective responses across multiple tumor types, whereas the control ADC showed limited activity. No clear association was observed between B7-H3 protein expression and therapeutic response. These findings demonstrate broad preclinical efficacy of vobra-duo in pediatric solid tumors and support further clinical investigation of B7-H3-targeted therapies in children.
2026-03-13 | Trefoil Factor-3 Is a Hypoxia-Triggered Pro-Tumorigenic Factor in Hepatoblastoma.
Hepatoblastoma (HB) is the most common malignant liver tumour in children. Despite improved survival in low-risk disease, outcomes for advanced or relapsed HB remain poor, emphasising the need for new therapeutic targets. Hypoxia, a hallmark of aggressive tumours, has recently been implicated in HB pathogenesis, but the molecular mechanisms involved are unclear. This study aimed to characterise the hypoxia-driven transcriptomic landscape of HB and identify key mediators of tumour progression. Transcriptomic analyses of HB cell lines cultured under normoxic and hypoxic conditions were combined with bioinformatic interrogation of public HB datasets, immunohistochemistry of human and murine tumours and plasma ELISA assays. Functional roles of trefoil factor 3 (TFF3) were evaluated through overexpression and shRNA-mediated knockdown in vitro and in a β-catenin/YAP-driven mouse model of HB. Hypoxia induced broad transcriptional reprogramming in HB cells, including significant upregulation of TFF3, a secreted oncogenic peptide. TFF3 expression was elevated in HB tissues and plasma, and colocalized with hypoxia marker carbonic anhydrase 9 (CA9). TFF3 promoted proliferation, anchorage-independent growth and cisplatin resistance under both normoxia and hypoxia. Knockdown of murine Tff3 suppressed tumour formation and angiogenesis in vivo. Transcriptomic and molecular analyses revealed that TFF3 sustains C-MYC expression and modulates mTOR/GSK3β signalling. TFF3 is a hypoxia-inducible factor that enhances HB cell proliferation, survival and chemoresistance. Its tumour-promoting activity through C-MYC and mTOR pathways identifies TFF3 as a potential therapeutic target and circulating biomarker in hepatoblastoma.
2026-02-02 | Hepatoblastoma brain metastasis treated with stereotactic radiosurgery: Illustrative case and literature search.
Hepatoblastoma (HB) is the most prevalent pediatric liver malignancy, typically affecting children under 5 years of age. Although advances in multimodal therapy, including surgical resection and chemotherapy, have significantly improved survival rates, distant metastases, particularly to the lungs and the brain, remain a critical prognostic challenge. Brain metastases (BMs) from HB are exceedingly rare, with only a limited number of cases reported in the literature, and the management of these lesions is challenging. Stereotactic radiosurgery (SRS) is an increasingly popular treatment option for BM due to its ability to deliver high doses of radiation to the target volume with minimal exposure to surrounding normal tissues. In this paper, we present a rare case of HB with brain metastasis that was treated with SRS for the 1st time. The case was a 4-year-old male with a history of stage IV HB who was diagnosed with a single BM. Post-treatment magnetic resonance images following SRS revealed a reduction in lesion size on 6th-month follow-up imaging and then a stable lesion on further follow-up imaging. The case highlights the potential efficacy of SRS as a treatment option for BM from HB and supports its usage in the management of this complex condition. The progression-free survival was 17 months, and the overall survival was 84 months. SRS may represent a safe and effective treatment modality for HB BM, particularly in patients who are not suitable candidates for surgical resection or systemic therapy. Larger studies with extended follow-up are necessary to more accurately assess the long-term safety, efficacy, and clinical utility of SRS in the management of HB-related BM.
2025-11-01 | Myeloid derived suppressor cell depletion for the treatment of hepatoblastoma 4283
Abstract Description Introduction Hepatoblastoma (HB) is the most common form of liver cancer in childhood. Neutrophilic myeloid derived suppressor cells (PMN-MDSCs) are immunosuppressive cells recruited to liver tumors. Depletion of PMN-MDSCs has not been studied as immunotherapy for HB. Methods HB was induced in C57BL/6 or FVB/N mice using hydrodynamic tail vein injection of YAP and β-catenin plasmids. Anti-Ly6G, CXCR2 inhibitor (CXCR2i), and/or anti-PD1 were administered IP. Liver immune cells were isolated using density gradient centrifugation in Percoll. Results Anti-Ly6G administration caused a reduction in tumor weight, an increase in CD8+ T cells, an increase in the proliferation of CD8+T cells, and CD44+CD8+ activated T cells. Administering a combination of CXCR2i and anti-PD1 showed incomplete PMN-MDSC depletion, an increase in CD4+ T cells, an increase in activated CD44+CD4+ cells, and a decrease in frequency of naive CD4+CD62L+ cells, suggesting a helper T-cell driven antitumor response. Conclusion PMN-MDSC depletion has potential as a treatment for HB. We will further leverage this treatment strategy in combination with anti-PD1 checkpoint inhibition to assess its effect on HB. Funding Sources National Institute On Minority Health And Health Disparities of the National Institutes of Health under Award Number U54MD007601 (Ola HAWAII), The Chun Foundation, Andrew and Mary Weinberg Foundation Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
small molecules
2026-09-18 | Novel 3D models for β-catenin-driven liver cancers.
Constitutive activation of β-catenin is a key feature in the pathogenesis of HCC and hepatoblastoma (HB). Activating alterations in the CTNNB1 gene and, to a lesser extent, inactivating alterations in the APC gene are observed in 30-40% of HCC cases and 80-90% of HB cases. For both tumours, therapeutic management remains suboptimal. Therefore, relevant experimental models are needed to improve our understanding and to test new therapeutic approaches. Liver organoids (n=17 mice) and tumouroids (n=14 mice) were established from APCΔhep and βcatΔex3 mouse models, which are clinically relevant models for β-catenin-activated HCC and mesenchymal HB. We developed a new methodological approach based on dynamic suspension culture in a rotating bioreactor. Morphological and molecular characteristics, as well as drug responses were evaluated by histology, immunohistochemistry, immunofluorescence, transcriptomics and RT-qPCR. This easy-to-implement methodology allows for the rapid production of large numbers of uniform organoids and tumouroids (30-75 per tumour) with no detectable cell death and hypoxia in their core. The robustness of the approach is also illustrated by the preservation of histological architecture, cell diversity (tumour cells, macrophages, endothelial cells) and gene expression in organoids and tumouroids compared with native liver tissue. Gene set enrichment analysis showed significant enrichment of 10 human HCC/HB tumour signatures in murine tumouroids. Organoids and tumouroids showed expected responsiveness to specific inhibitors, including the β-catenin antagonist WNTinib. These organoids and tumouroids represent robust in vitro models of β-catenin-driven HCC and mesenchymal HB. They provide a scalable platform for drug screening and may support the development of "à la carte" therapies urgently needed for these indications. Impact and implications; This study addresses the need for representative in vitro models to investigate β-catenin-driven liver cancers. The tumouroids developed here provide robust and reproducible 3D models that closely recapitulate the histological features, cellular diversity, and gene expression profiles of native liver tumours. These models offer a valuable platform for studying tumour biology, evaluating therapeutic candidates, and supporting the development of personalized treatment strategies. They may also contribute to reducing the use of animals in preclinical research.
2026-09-15 | Tumor Topography Remodels TME Signalling via Compartment-Specific Host-Microbiome-Tumor Crosstalk in Hepatoblastoma.
Background & Aims: Signaling within the tumor microenvironment (TME) emerges from dynamic crosstalk among cancer cells, host tissues, and the microbiome. Orthotopic and ectopic xenograft models are widely used in preclinical liver cancer research, yet it remains unclear to what extent tumor location shapes systemic host responses and gut-liver communication. We therefore investigated how anatomical context influences host transcriptomes and spatially resolved intestinal microbial ecosystems in hepatoblastoma (HB). Methods: We integrated bacterial/archaeal ecology with host and xenograft transcriptomes in orthotopic versus ectopic hepatoblastoma xenografts in male athymic CAnN.Cg-Foxn1nu/Crl mice. Single-sample GSEA, sparsity-aware networks, and DIABLO multi-block integration mapped pathway-level coordination across intestinal segments, stool, secondary lymphoid organs, livers, and tumors. Results: Tumor localization was associated with compartment-specific differences in host signaling, with the mesenteric lymph node and liver showing prominent shifts in TNFA/NF-κB, hypoxia, unfolded protein response, xenobiotic metabolism, mTORC1, KRAS, epithelial-mesenchymal transition, and MYC/E2F cell-cycle axes. Archaea exhibited pronounced, niche-specific signatures that showed positive correlations with proliferative and inflammatory Hallmarks and negative correlations with interferon pathways. Multi-omics integration (r ≥ 0.85) indicated coordinated variation linking specific microbial families to host and tumor programs and positioned the xenograft block as a hub connecting EMT, mTORC1, and angiogenesis to defined archaeal and bacterial taxa. Conclusions: Tumor topography remodels TME signaling through compartment-dependent host-microbiome-tumor crosstalk, with archaeal domains emerging as salient correlates of proliferative and stress-response networks. These findings provide a systems framework and testable hypotheses for therapeutic modulation of TME signaling via interkingdom interactions.
2026-08-27 | Treatment Adaptation to Surgical Timing in Pediatric Hepatoblastoma: A 19-Year Single-Center Experience With Resection and Liver Transplantation.
The management of hepatoblastoma (HB) relies on chemotherapy combined with surgery, either liver resection (LR) or liver transplantation (LT), with reported overall survival (OS) of 80%, cardiac toxicity of 6%, nephrotoxicity of 21%, ototoxicity of 32%-46%. In clinical practice, deviations from protocol-defined chemotherapy are often required to achieve resectability or bridge to transplantation. We aimed to evaluate the impact of treatment adaptation to surgical timing on OS and toxicity in a selected group of patients referred to a transplantation center. We retrospectively analyzed patients with HB treated according to SIOPEL protocols at our center between 2004 and 2022. We collected clinical data, focusing on deviations from protocol-specified therapy, timing of medical and surgical treatment, OS, treatment-related toxicities (left ventricular ejection fraction, LVEF< 50%, estimated glomerular filtration rate, eGFR< 90 mL/mL/m2, increased hearing threshold of 20-40 dB at 4 kHz). Forty-two patients, median age at diagnosis 1.9 years (IQR 0.7-3.5), 16/42 (38.1%) with metastatic disease, 24/42 (57.1%) with vascular involvement were recorded. Additional chemotherapy beyond protocol indications, due to persistent pulmonary metastases, delayed organ availability, or disease progression was administered to 17/20 (85%) who underwent first-line LT and 10/22 (45%) who underwent LR (p = 0.007). Death occurred in 3/20 (15%) versus 7/22 (31.8%) (p = 0.2) respectively. After median follow-up of 4.5 years (IQR 1.2-6.2) OS is 32/42 (71.4%); cardiotoxicity developed in 1/42 (2.4%), nephrotoxicity in 8/42 (19%), ototoxicity in 9/42 (21.4%). A large proportion of patients with HB require adaptation of protocol-specified therapy, especially LT candidates. This favors successful management and is not associated with increased toxicity compared to previous reports.
2026-08-14 | Antimicrobial, anti-biofilm, and anticancer activities of green-synthesized silver nanoparticles using Crossostephium chinense (L.) Makino aqueous leaf extract.
The increasing burden of infectious diseases, driven by microbial pathogenicity and antimicrobial resistance, necessitates the development of effective and sustainable antimicrobial strategies. In that context, this study reports, for the first time, the green synthesis of silver nanoparticles (AgNPs) using an aqueous extract of Crossostephium chinense (L.) Makino (CC) leaves, wherein plant-derived phytochemicals act as natural reducing and capping agents. Mass spectrometric analyses of CC aqueous leaf extract identified 62 possible metabolites, including flavonoids, phenolics, and terpenoids, that possibly facilitate nanoparticle synthesis. The synthesized C. chinense-derived silver nanoparticles (CC-AgNPs) were characterized as moderately stable, crystalline, spherical with sizes ranging from 20-80 nm. CC-AgNPs displayed broad-spectrum antimicrobial activity, showing the greatest susceptibility in Bacillus subtilis and Pseudomonas aeruginosa, with a minimum inhibitory concentration (MIC) of 6 μg/mL, while electron microscopy confirmed severe structural damage to bacterial membranes. Furthermore, CC-AgNPs displayed strong antibiofilm activity, achieving up to 92% biofilm inhibition in B. subtilis at 12 μg/mL. The anticancer potential of CC-AgNPs was evaluated against breast cancer (MCF-7 and MDA-MB-231), chronic myelogenous leukemia (K562), and hepatoblastoma (HepG2) cell lines. Among these, MDA-MB-231 cells were the most sensitive, exhibiting the lowest IC50 value. Further mechanistic investigations in MDA-MB-231 cells demonstrated apoptosis induction, as evidenced by nuclear fragmentation, Annexin V/PI staining and activation of caspases. In conclusion, these findings highlight CC-AgNPs as promising candidates for antimicrobial, antibiofilm, and anticancer applications.
2026-08-13 | [Efficacy comparisons of chemotherapy regimens with different intensities in high-risk pediatric hepatoblastoma].
Objective: To evaluate the efficacy of different chemotherapy regimens in children with high-risk hepatoblastoma (HB). Methods: A retrospective cohort study was conducted on 99 patients under 18 years old with high-risk HB treated at Sun Yat-sen University Cancer Center between December 2004 and July 2024. The patients were divided into three groups: the PLADO regimen (cisplatin in combination with doxorubicin, n=27), the C5VD/IIV regimen (alternating cycles of cisplatin/5-flourouracil/vincristine/doxorubicin with irinotecan/ifosfamide/vincristine, n=29), and the modified SIOPEL-4 regimen (the original SIOPEL-4 regimen with omitted high-dose cisplatin on day15, n=43). Short-term efficacy, adverse effects, and long-term survival were compared among the three groups. Results: The objective response rates for the PLADO, C5VD/IIV, and modified SIOPEL-4 groups were 73.9% (17/23), 70.8% (17/24), and 88.6% (31/35), respectively, with no statistically significant difference among the three groups (P=0.190). The disease control rates were 82.6% (19/23), 83.3% (20/24), and 100.0% (35/35), the 3-year progression-free survival (PFS) rates were 19.2%, 37.0%, and 56.7%, and the 3-year overall survival (OS) rates were 69.2%, 55.6%, and 79.0%, respectively. The modified SIOPEL-4 group showed significantly better disease control rate and PFS rate compared withthe other two groups (both P＜0.05). After merging the PLADO and C5VD/IIV groups, the modified SIOPEL-4 group demonstrated significantly superior PFS and OS rates (both P＜0.05). Conclusions: The efficacy of modified SIOPEL-4 regimen in treating high-risk HB is superior compared with those of PLADO and C5VD/IIV regimens, but there remains room for further improvement in efficacy. Intensifying supportive care and pursuing aggressive local therapies, especially upfront liver transplantation for locally inoperable tumors, may further improve outcomes.
proteins
2026-04-06 | Overexpression of ONECUT1 suppresses hepatoblastoma progression via modulating tumor cell growth and tumor microenvironment.
Hepatoblastoma is the most common malignant liver tumor in children. Our previous work showed that enforced expression of the transcription factor One Cut Homeobox 1 (ONECUT1) suppresses the initiation of hepatoblastoma. However, it remains unclear whether increasing ONECUT1 expression can also inhibit tumor progression after tumors have already formed. The purpose of this study was to determine the effects of ONECUT1 induction on tumor cell behavior and tumor growth during established hepatoblastoma progression. We generated doxycycline-inducible expression systems to upregulate ONECUT1 in hepatoblastoma cells in culture and in mouse models. In human hepatoblastoma cells, induction of ONECUT1 promoted apoptotic cell death and reduced cell cycle progression. In a subcutaneous xenograft model using immunodeficient mice, ONECUT1 induction slowed tumor growth but did not cause tumor regression. We then established an orthotopic HB model in FVB/N mice by tail-vein injection of YAP/β-catenin/TRE-ONECUT1 plasmids. ONECUT1 expression in existing mouse HB cells was induced by feeding the mice with DOX-water. Remarkably, tumor regression was observed following ONECUT1 induction. Histological analyses showed extensive necrosis and apoptosis in tumor lesions following induction of ONECUT1, accompanied by robust macrophage infiltration and moderate T cell infiltration. Depletion of T cells using antibodies against CD4 and CD8 weakened the antitumor effect of ONECUT1, indicating that T-cell activity contributes to tumor suppression. Transcriptomic analysis further suggested that ONECUT1 may promote antitumor immune responses in part by increasing expression of immune-related cytokines. Induction of ONECUT1 suppresses hepatoblastoma progression by inhibiting tumor cell growth and by reshaping the tumor immune microenvironment. These findings reveal a previously unrecognized antitumor role of ONECUT1 during hepatoblastoma progression and suggest that restoring ONECUT1 activity may represent a promising therapeutic strategy for this pediatric malignancy.
2026-01-05 | Disrupting the Formation of YAP Condensates Promotes the Activation of AMPKα to Inhibit the Progression of Primary Liver Cancer.
Liquid-liquid phase separation, a process facilitating biomolecular condensate formation, plays a critical role in various pathologies, including tumorigenesis, metabolic disorders, and neurodegenerative diseases. Dysregulated phase separation has been linked to tumor initiation and progression. However, the pathological significance of phase separation in primary tumors of mice remains largely unexplored. We constructed a series of primary liver cancer models via hydrodynamic tail vein injection and confirmed that endogenous Yes-associated protein (YAP) formed numerous condensates in primary liver cancer of mice. Deletion, mutagenesis, and replacement assays confirmed that the formation of YAP condensates plays a critical role in the development of cellular myelocytomatosis oncogene (c-Myc)-induced hepatocellular carcinoma, myristoylated AKT (myr-AKT)-induced intrahepatic cholangiocarcinoma, and amino-terminal missing first 90 amino acids of catenin beta 1 (ΔN90-CTNNB1)-induced hepatoblastoma. We found that the YAP phase separation inhibits the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, thereby promoting the occurrence and development of primary liver cancer. Additionally, we identified that the TEA domain transcription factor 1 (TEAD1)-derived peptide effectively disrupted YAP condensate formation, leading to AMPKα activation in vivo and inhibition of primary liver cancer progression. This study systematically confirms that YAP phase separation plays a crucial role in the progression of various primary liver cancers and further substantiates that strategic disruption of these condensates constitutes an effective treatment for primary liver cancer in vivo.
2024-12-06 | Single-Cell RNA Sequencing Reveals LEF1-Driven Wnt Pathway Activation as a Shared Oncogenic Program in Hepatoblastoma and Medulloblastoma
(1) Background: Hepatoblastoma and medulloblastoma are two types of pediatric tumors with embryonic origins. Both tumor types can exhibit genetic alterations that affect beta-catenin and Wnt pathway; (2) Materials and Methods: This study used bioinformatics and integrative analysis of multi-omics data at both the tumor and single-cell levels to investigate these two distinct pediatric tumors: medulloblastoma and hepatoblastoma; (3) Results: Cross-transcriptome analysis revealed a commonly regulated expression signature between hepatoblastoma and medulloblastoma tumors. Among the commonly upregulated genes, the transcription factor LEF1 was significantly expressed in both tumor types. In medulloblastoma, LEF1 upregulation is associated with the WNT-subtype. Analysis of LEF1 genome binding occupancy in H1 embryonic stem cells identified 141 LEF1 proximal targets activated in WNT-medulloblastoma, 13 of which are involved in Wnt pathway regulation: RNF43, LEF1, NKD1, AXIN2, DKK4, DKK1, LGR6, FGFR2, NXN, TCF7L1, STK3, YAP1, and NFATC4. An expression score based on these 13 WNT-LEF1 targets accurately predicted the WNT-subtype in two independent medulloblastoma transcriptome cohorts. At the single-cell level, the WNT-LEF1 expression score was exclusively positive in WNT-medulloblastoma tumor cells. This WNT-LEF1-dependent signature was also confirmed as activated in the hepatoblastoma tumor transcriptome. At the single-cell level, the WNT-LEF1 expression score was higher in tumor cells from both human hepatoblastoma samples and a hepatoblastoma patient-derived xenotransplant model; (4) Discussion: This study uncovered a shared transcriptional activation of a LEF1-dependent embryonic program, which orchestrates the regulation of the Wnt signaling pathway in tumor cells from both hepatoblastoma and medulloblastoma.
2024-10-03 | Gas1-Mediated Suppression of Hepatoblastoma Tumorigenesis
Background and Aims: Hepatoblastoma (HB), the most common pediatric liver cancer, often dysregulates the Wnt/β-catenin, Hippo and NFE2L2/NRF2 pathways. Pairwise combinations of oncogenically active forms of the terminal transcription factor effectors of these pathways, namely β-catenin (B), YAP (Y) and NRF2 (N) generate HBs in mice, with the triple combination (B+Y+N) being particularly potent. Each tumor group alters the expression of thousands of B-,Y- and N-driven unique and common target genes. Identifying those most responsible for transformation is thus an important question as it might reveal new mechanistic insights and therapeutic opportunities. Approach and Results: Transcriptional profiling of >60 murine HBs driven by the above oncogenic combinations and different B mutants and in genetic backgrounds that impair tumor growth rates but not initiation has revealed a common set of 22 "BYN genes" that are similarly deregulated in all cases. Many are associated with multiple "Cancer Hallmarks" and their expression levels often correlate with survival in human HBs, hepatocellular carcinomas and other cancers. Among the most down-regulated of these is Gas1, which encodes a Glycosylphosphatidylinositol (GPI)-linked outer membrane protein. We show here that restoring Gas1 expression impairs B+Y+N-driven HB tumor growth in vivo and in HB-derived immortalized cell lines in vitro in a manner than requires membrane anchoring of the protein via its GPI moiety. Conclusions: Our findings implicate Gas1 as a proximal mediator of HB pathogenesis and validate the BYN gene set as one deserving of closer additional scrutiny in future studies.
2024-09-05 | Abstract B024: Single cell transcriptomics and patient-derived tumoroids reveal that hepatobiliary lineage programs cooperate with Wnt pathway mutations to drive cell proliferation in hepatoblastoma
Abstract Cancers evolve not only through the acquisition and clonal transmission of somatic mutations but also by non-genetic mechanisms that modify cell phenotype. Such epigenetic causes of intra-tumoral heterogeneity may be particularly important in pediatric cancers with low rates of genomic mutations. Hepatoblastoma, the most common primary liver malignancy in children, has one of the lowest mutational burdens of all cancers, providing an ideal system to elucidate non-genetic mechanisms of intra-tumoral heterogeneity. Up to 80-90% of hepatoblastomas have activating mutations in CTNNB1 and the Wnt pathway. Yet, despite their simple genomics, these tumors exhibit significant histologic heterogeneity, including epithelial (embryonal and fetal histology) and mesenchymal components. Using transcriptomics and patient-derived tumoroids, we find that hepatobiliary lineage programs modulate the transcriptional outcome of mutated CTNNB1. A subset of cholangiocytic-like tumor cells express the growth factor FGF19, which promotes proliferation of neighboring cells in conjunction with activated Wnt signaling. To characterize the transcriptional profiles of the distinct histologic components of hepatoblastoma, we used laser capture microdissection to isolate tumor regions identified as embryonal, fetal, or mesenchymal histology, as well as adjacent normal liver. While all tumor regions showed increased expression of Wnt target genes as compared to normal liver, the embryonal components showed even higher expression of Wnt target genes as compared to the fetal components, as well as increased proliferation markers and higher expression of the embryonic biliary transcription factor SOX4. RNA in situ hybridization in primary hepatoblastomas revealed distinctive foci of embryonal hepatoblastoma cells that express the growth factor FGF19. These FGF19-expressing cells were surrounded by FGF19-negative cells that expressed KLB, the co-receptor for FGF19 signaling, and showed an increased proliferation. We therefore hypothesized that FGF19 acts in a paracrine fashion to drive cell cycle progression of hepatoblastoma cells in cooperation with constitutively active Wnt signaling. We further generated patient-derived tumoroids to systematically test the requirements for exogenous growth factors. We found that despite activated Wnt signaling, FGF19-negative tumor cells required additional exogenous growth factors to proliferate. In some tumoroids, subsets of cells expressed FGF19 endogenously, downstream of Wnt/beta-catenin and SOX4, acting as a paracrine signal. We conclude that the embryonic biliary transcription factor SOX4 cooperates with mutated beta-catenin, inducing FGF19 as a paracrine growth signal that can promote proliferation of FGF19-negative tumor cells. Thus, in this pediatric cancer presumed to originate from a multipotent hepatobiliary progenitor, lineage-driven heterogeneity results in a functional growth advantage, a non-genetic mechanism whereby developmental lineage programs influence tumor evolution, with implications for treatment. Citation Format: Peng V. Wu, Matt Fish, Florette K. Hazard, Chunfang Zhu, Sujay Vennam, Hannah Walton, Joanna Przybyl, Maurizio Morri, Norma Neff, Robert B. West, Roel Nusse. Single cell transcriptomics and patient-derived tumoroids reveal that hepatobiliary lineage programs cooperate with Wnt pathway mutations to drive cell proliferation in hepatoblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B024.
oligonucleotides
2026-09-10 | A 177Lu-Labeled Circular Bivalent Aptamer for PTK7-Targeting Radionuclide Therapy in Ovarian Cancer and Orthotopic Hepatoblastoma.
Targeted radionuclide therapy (TRT) is a promising strategy for precision oncology but is limited by the lack of high-performance targeting ligands. Here, we report a lutetium-177 (177Lu)-labeled PTK7-targeted cyclized bivalent aptamer (CBSgc8) for treating an orthotopic hepatoblastoma. The cyclized multivalent design enhances biostability and binding affinity, while 177Lu labeling preserves its functional properties. The resulting 177Lu-CBSgc8 exhibited high serum stability, strong specificity for PTK7-positive cells, efficient internalization, and dose-dependent cytotoxicity in vitro. In vivo, 177Lu-CBSgc8 inhibited tumor growth in an OVCAR3 ovarian cancer model, although tumor accumulation remained limited. Given its PTK7-targeting capability and preferential hepatic distribution, we further evaluated its therapeutic potential in an orthotopic HepG2 hepatoblastoma model. In this setting, 177Lu-CBSgc8 achieved 76.6% tumor growth inhibition with a favorable safety. These findings demonstrate the potential of exploiting tissue distribution characteristics together with molecular targeting to expand the applicability of aptamer-based TRTs.
2025-05-03 | Identification of a Growth-Promoting Gene Cluster in the Region 2q24 as a Driver of Tumorigenesis in Childhood Hepatoblastoma.
Hepatoblastoma (HB) represents the most common primary malignancy of the liver in childhood. Cytogenetic studies uncovered characteristic copy number alterations in HB. The frequent gain of chromosome 2q and particularly the recurrent 2q24 amplification suggest the presence of a so far unidentified oncogenic driver within this amplicon. Herein, high-resolution copy number profiles from 76 patients with HB were generated by using molecular inversion probe array technology. 2q gain was present in 63.2%, and 2q24 high-gain/amplification was present in 14.5% of patients analyzed. In the smallest overlapping region at 2q24.2q24.3, spanning >5.2 Mbp, 22 protein-coding genes, 2 long noncoding RNA genes, and one miRNA gene were mapped. RNA expression analysis of these smallest overlapping region genes identified RBMS1, BAZ2B, MARCH7, DPP4, FIGN, and TANK as overexpressed in 2q24 high-gain/amplified HB cases. Accordingly, these six genes were selected for further investigation. In situ, immunohistochemical staining showed higher protein expression of these genes in 2q24 high-gain HB tissue sections. In vitro, functional analyses were performed in established human HB cell lines carrying a 2q (high-)gain. Knockdown of these genes by specific siRNAs resulted in reduced proliferation and marked reduction of Wnt pathway activity. These genes located within the 2q24 amplicon might collaborate in driving cellular growth by interaction with the Wnt pathway that is known to be activated pathologically in HB.
2024-09-09 | N6-methyladenosine modification of LATS2 promotes hepatoblastoma progression by inhibiting ferroptosis through the YAP1/ATF4/PSAT1 axis.
Ferroptosis has attracted extensive interest from cancer researchers due to its substantial potential as a therapeutic target. The role of LATS2, a core component of the Hippo pathway cascade, in ferroptosis initiation in hepatoblastoma (HB) has not yet been investigated. Furthermore, the underlying mechanism of decreased LATS2 expression remains largely unknown. In the present study, we demonstrated decreased LATS2 expression in HB and that LATS2 overexpression inhibits HB cell proliferation by inducing ferroptosis. Increased LATS2 expression reduced glycine and cysteine concentrations via the ATF4/PSAT1 axis. Physical binding between YAP1/ATF4 and the PSAT1 promoter was confirmed through ChIP‒qPCR. Moreover, METTL3 was identified as the writer of the LATS2 mRNA m6A modification at a specific site in the 5' UTR. Subsequently, YTHDF2 recognizes the m6A modification site and recruits the CCR4-NOT complex, leading to its degradation by mRNA deadenylation. In summary, N6-methyladenosine modification of LATS2 facilitates its degradation. Reduced LATS2 expression promotes hepatoblastoma progression by inhibiting ferroptosis through the YAP1/ATF4/PSAT1 axis. Targeting LATS2 is a potential strategy for HB therapy.
2024-08-07 | From diagnosis to therapy: The critical role of lncRNAs in hepatoblastoma.
According to findings, long non-coding RNAs (lncRNAs) serves an integral part in growth and development of a variety of human malignancies, including Hepatoblastoma (HB). HB is a rare kind of carcinoma of the liver that mostly affects kids and babies under the age of three. Its manifestations include digestive swelling, abdominal discomfort, and losing weight. This thorough investigation digs into the many roles that lncRNAs serve in HB, giving views into their varied activities as well as possible therapeutic consequences. The function of lncRNAs in HB cell proliferation, apoptosis, migratory and penetrating capacities, epithelial-mesenchymal transition, and therapy tolerance is discussed. Various lncRNA regulatory roles are investigated in depth, yielding information on their effect on essential cell processes such as angiogenesis, apoptosis, immunity, and growth. Circulating lncRNAs are currently acknowledged as potential indications for the initial stages of identification of cancer, with the ability to diagnose as well as forecast. In addition to their diagnostic utility, lncRNAs provide curative opportunities as locations and actors, contributing to the expanding landscape of cancer research. Several HB-linked lncRNAs have been demonstrated to exhibit abnormal expression and are involved in tumor-like characteristics via DNA, RNA, or protein binding or encoding short peptides. As a result, a better knowledge of lncRNA instability might bring fresh perspectives into HB etiology as well as innovative strategies for HB early diagnosis and therapy. We describe the abnormalities of lncRNA expression in HB and their tumor-suppressive or carcinogenic activities during HB carcinogenesis in this study. Furthermore, we explore lncRNAs' diagnostic and therapeutic possibilities in HB.
2024-06-12 | MicroRNA-141-regulated KLK10 and TNFSF-15 gene expression in hepatoblastoma cells as a novel mechanism in liver carcinogenesis.
Liver cancer is one of the most pivotal global health problems, leading hepatocellular carcinoma (HCC) with a significant increase in cases worldwide. The role of non-coding-RNA in cancer proliferation and carcinogenesis has attracted much attention in the last decade; however, microRNAs (miRNAs), as non-coding RNA, are considered master mediators in various cancer progressions. Yet the role of miR-141 as a modulator for specific cellular processes in liver cancer cell proliferation is still unclear. This study identified the role of miR-141 and its potential functions in liver carcinogenesis. The level of miR-141 in HepG2 and HuH7 cells was assessed using quantitative real-time PCR (qRT-PCR) and compared with its expression in normal hepatocytes. A new miR-141 construct has been performed in a CMV promoter vector tagged with GFP. Using microarray analysis, we identified the potentially regulated genes by miR-141 in transfected HepG2 cells. The protein profile of the kallikrein-related peptidase 10 (KLK10) and tumor necrosis factor TNFSF-15 was investigated in HepG2 cells transfected with either an inhibitor, antagonist miR-141, or miR-141 overexpression vector using immunoblotting and flow cytometry assay. Finally, ELISA assay has been used to monitor the produced inflammatory cytokines from transfected HepG2 cells. Our findings showed that the expression of miR-141 significantly increased in HepG2 and HuH7 cells compared to the normal hepatocytes. Transfection of HepG2 cells with an inhibitor, antagonist miR-141, showed a significant reduction of HepG2 cell viability, unlike the transfection of miR-141 overexpression vector. The microarray data of HepG2 cells overexpressed miR-141 provided a hundred downregulated genes, including KLK10 and TNFSF-15. Furthermore, the expression profile of KLK10 and TNFSF-15 markedly depleted in HepG2 cells transfected with miR-141 overexpression accompanied by a decreasing level of interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α), indicating the role of miR-141 in HepG2 cell proliferation and programmed cell death. Interestingly, the experimental rats with liver cancer induced by Diethylnitrosamine injection further confirmed the upregulation of miR-141 level, IL-10, and TNF-α and the disturbance in KLK10 and TNFSF-15 gene expression compared with their expression in normal rats. The in-silico online tools, IntaRNA and miRWalk were used to confirm the direct interaction and potential binding sites between miR-141 and identified genes. Thus, the seeding regions of potential targeted sequences was cloned upstream of luciferase reporter gene in pGL3 control vector. Interestingly, the luciferase activities of constructed vectors were significantly decreased in HepG2 cells pre-transfected with miR-141 overexpression vector, while increasing in cells pre-transfected with miR-141 specific inhibitor. In summary, these data suggest the crucial role of miR-141 in liver cancer development via targeting KLK10 and TNFSF-15 and provide miR-141 as an attractive candidate in liver cancer treatment and protection.
cell therapies
2026-09-09 | Complete Regression of Hepatoblastoma after Interleukin-15– and Interleukin-21–Coexpressing CAR T-Cell Therapy
A 3-year-old boy with chemotherapy-resistant metastatic hepatoblastoma had complete regression lasting at least 12 months after two infusions of glypican-3–specific CAR T cells coexpressing interleukin-15 and interleukin-21.
2026-06-27 | T-cell receptor-engineered T-cell therapy using a glypican-3-specific TCR derived from a hepatoblastoma vaccine responder for HLA-A2-positive glypican-3-expressing cancers.
Glypican-3 (GPC3) is highly expressed in most hepatocellular carcinomas (HCCs) and hepatoblastoma, shows minimal expression in non-tumor adult tissues, and is also detected in several other malignancies, making it an ideal target for anticancer immunotherapy. We previously demonstrated in clinical trials that GPC3 peptide vaccination can induce durable antitumor immunity in patients with HCC and pediatric hepatoblastoma and established human leukocyte antigen (HLA)-A∗02:01-restricted GPC3-specific cytotoxic T lymphocyte (CTL) clones. In this study, we isolated high-avidity T-cell receptors (TCRs) from CTL clones established from a pediatric hepatoblastoma patient who achieved long-term recurrence-free survival for more than 10 years after surgical resection of pulmonary metastases followed by GPC3 peptide vaccination. Using a retroviral vector incorporating endogenous TCR suppression, these TCR genes were introduced into primary human T cells to generate GPC3-specific TCR-engineered T cells (TCR-T cells). These TCR-T cells exhibited GPC3-specific recognition and significant cytotoxicity against GPC3-positive tumor cells in vitro, while showing minimal activity against GPC3-negative targets. Moreover, GPC3-specific TCR-T cells migrated to tumor sites, resulting in the prevention of tumor engraftment as well as tumor growth suppression and stabilization in xenograft models. GPC3-targeted TCR-T cells derived from CTLs induced by GPC3 peptide vaccination demonstrated potent antitumor activity against HLA-A∗02-positive and GPC3-positive cancers. These findings provide an important rationale for Phase I clinical trials of GPC3-targeted TCR-T cells as a promising therapeutic strategy for GPC3-expressing solid tumors, including HCC and refractory hepatoblastoma.
2026-06-01 | Excellent Outcomes With High-Risk Pediatric Hepatoblastoma: A Detailed Analysis of a Large, Single-Center Experience.
Hepatoblastoma (HBA) is a rare pediatric malignancy treatable with liver transplantation (LTx). Limited data exist on outcomes after LTx for HBA. This study evaluates the therapeutic efficacy of LTx in pediatric patients with HBA, delineates principal complications, and assesses long-term psychosocial outcomes. This retrospective cohort study analyzed a prospectively maintained database of children undergoing LTx for HBA at a single US center from 1984 to 2025. Primary outcomes were patient and graft survival at 1, 5, and 10 years post-LTx and HBA recurrence. Secondary outcomes included post-LTx complications, recurrence predictors, and psychosocial parameters. Of 55 patients (60% female; 40% Hispanic; mean age at diagnosis, 36 months), most had PRETEXT stage III (44%) or IV (47%) disease; mean α-fetoprotein level at diagnosis was 569 355 ng/mL. All but 1 received chemotherapy; 15 (27%) had pre-LTx resection. Mean wait time to LTx was 10 months. Pre-LTx metastatic disease (pulmonary) was present in 5 patients (9%). Explant pathology showed macrovascular invasion (n = 16), positive lymph nodes (n = 3), and extra-hepatic tumor invasion/rupture (n = 2). Post-LTx complications included HBA recurrence (20%), hepatic artery thrombosis (11%), and biliary stricture (20%). Patient survival was 89% at 1 year, 74% at 5 and 10 years; graft survival was 89%, 73%, and 73%, respectively. Significant predictors of recurrence were older age at LTx (p = 0.01), longer waiting time to LTx (p = 0.02), prior resection (p = 0.01), larger tumor size (p = 0.03), vascular invasion (p = 0.02), and utilization of a segmental graft (p = 0.002). Mortality was mainly due to recurrence. Psychosocially, 14 patients needed special education, 10 had developmental delays, 5 of 12 adults completed high school, 2 earned college degrees, and 3 are employed. This large single-center study demonstrates favorable survival after LTx for high-risk HBA. Recurrence predictors support avoiding pre-LTx resection in high-risk cases. While living donor or split grafts can expedite transplantation, segmental grafts were independently linked to higher recurrence. Notably, metastases at diagnosis did not increase recurrence, supporting aggressive treatment. The rate of HAT and biliary stricture was significantly higher for children transplanted for HBA than for our overall pediatric experience. These findings help guide the management of this rare malignancy.
2025-12-04 | Identification of CD7 as a novel biomarker of embryonal hepatoblastoma.
This study aimed to investigate the expression of cluster of differentiation 7 (CD7) in hepatoblastoma (HB) and its potential use as a novel biomarker of HB. CD7 expression was investigated in human HB samples at the gene level by bulk, single-cell RNA sequencing, and spatial transcriptomic analyses, in addition to the protein level by immunohistochemical (IHC) staining. CD7 gene expression-based survival analysis was also conducted, along with gene set enrichment analysis (GSEA) of the CD7-SECTM1 receptor-ligand gene pair. CD7 was differentially expressed in human HB at both the gene level by various bioinformatics analyses, and the protein level by IHC, with remarkably higher expression levels in embryonal HB. Conversely, CD7 was not expressed in other primary adult liver tumors. CD7high HB cases showed poorer 5-year event-free survival (P = 0.016), and GSEA demonstrated that CD7 is linked to the embryonal MYCN transcription factor, as were protumor kinases such as JAK3, and marginally MAPK14 and MAPK3. CD7 is expressed in human HB, especially the embryonal histological subtype, and appears to be linked to tumor progression and poor clinical outcomes. Nevertheless, CD7-targeted chimeric antigen receptor T cells could be proposed as a promising immunotherapy for embryonal HB.
2025-10-11 | Claudin 6 is a suitable target for CAR T-cell therapy in atypical teratoid/rhabdoid brain tumors and other pediatric solid tumors.
Solid tumors comprise approximately 60% of all pediatric cancers. Relapsed or refractory tumors of the central nervous system (CNS), such as atypical teratoid/rhabdoid tumors (AT/RTs), are the leading cause of death in children with cancer. Claudin 6 (CLDN6)-specific chimeric antigen receptor (CAR) T cells have demonstrated activity in preclinical and clinical studies in various solid adult cancers. However, the suitability of CLDN6 as a target in pediatric tumors and their susceptibility to CAR T-cell therapy has yet to be established. This study aimed to evaluate the suitability of CLDN6 as a target for CAR T-cell therapy of pediatric solid tumors. Immunohistochemical CLDN6 expression was assessed in fetal normal tissues (n=91), pediatric normal tissues (n=157), and two sets of pediatric tumor tissues (n=527 and n=49) using a combined score that includes the percentage of stained cells with a 4-point intensity scale (0 to 3+). The antitumor activity of CLDN6 RNA-transduced CAR T cells against AT/RT cell lines was assessed with in vitro assays and in immunodeficient NOD-SCID-γc-/- (NSG) mouse models bearing orthotopic xenograft tumors. Membranous CLDN6 expression, as detected by immunohistochemistry, was widely observed in fetal tissues but was absent in almost all non-malignant pediatric tissues, except for very rare, scattered cells with 1+ to 2+ intensity in kidney, pancreas, pituitary, and salivary gland tissues. Membranous CLDN6 expression was frequently detected in a subset of the pediatric tumor entities, including germ cell tumors (93% of samples with CLDN6-positive cells), nephroblastoma (64%), extracranial malignant rhabdoid tumors (50%), and AT/RTs (39%). In CLDN6-positive samples, CLDN6 was generally expressed with 2+ or 3+ intensity in substantial proportions of the cancer cells. Strong CLDN6 expression was also detected in single samples of hepatoblastoma, Ewing sarcoma/other embryonal tumors, and osteosarcoma.In experimental models, CLDN6-CAR T cells led to antigen-specific killing of endogenously CLDN6-expressing AT/RT cell lines in vitro and exhibited potent and specific antitumor activity in mice bearing orthotopic CLDN6-expressing AT/RT xenograft tumors. These results support CLDN6 as an oncofetal cell-surface antigen that may be suitable for CAR T-cell targeting in pediatric solid tumors, including those of the CNS.
other
2026-06-11 | Macrophage Polarization and Spatial Architecture Characterize the Tumor Immune Microenvironment and Prognosis in Hepatoblastoma.
Hepatoblastoma, the most common primary pediatric liver malignancy, exhibits resistance to contemporary treatments in a subset of patients. Understanding the tumor immune microenvironment is essential for the development of novel immuno-oncological therapies. Herein, the microenvironment of hepatoblastoma was characterized by mapping the spatial distribution of immune cells, identifying prognostic immune features, assessing chemotherapy-induced alterations, and exploring potential immunotherapeutic targets. Whole-slide multiplex immunofluorescence staining (n = 35) was performed on formalin-fixed, paraffin-embedded hepatoblastoma specimens from 25 patients. Immune cell densities were analyzed in precytotoxic and post-cytotoxic treatment samples. Spatial characteristics were assessed using nearest-neighbor distances and Gcross functions, and differential protein abundance patterns were identified using quantitative proteomics (n = 18). This study revealed a predominantly myeloid-rich microenvironment in hepatoblastoma. Macrophages shifted toward a proinflammatory state following cytotoxic treatment. Proinflammatory phosphorylated STAT1 (pSTAT1)+ macrophages were associated with improved patient survival when retained in proximity to tumor cells after chemotherapy. Down-regulation of extracellular matrix pathways was observed in these pSTAT1-rich samples. Common lymphatic endothelial and vascular endothelial receptor 1 (CLEVER-1), an immunosuppressive marker and potential therapeutic target, was abundantly expressed, particularly in stromal macrophages. This study highlights the significance of macrophage phenotypes in hepatoblastoma and their potential as a therapeutic target. Moreover, the findings underline the prognostic value of pSTAT1+ macrophages and CLEVER-1 as a promising immunotherapy target. Future research should explore combination strategies to exploit chemotherapy-induced shifts in macrophage polarization.
2026-04-06 | PRECLINICAL ACTIVITY OF THE B7-H3- TARGETING ANTIBODY-DRUG CONJUGATE (ADC) VOBRAMITAMAB DUOCARMAZINE (VOBRA DUO) IN PEDIATRIC SOLID TUMORS.
Vobramitamab duocarmazine (vobra-duo) is a duocarmycin-based, humanized antibody-drug conjugate (ADC) targeting B7-H3, with a drug-to-antibody ratio of ~2.7. Vobra-duo has demonstrated robust antitumor activity in multiple adult cancer models, along with favorable pharmacokinetic and safety profiles in cynomolgus monkeys. Early results from phase I/II clinical trials (NCT03729596) have shown manageable toxicity and promising objective responses in patients with metastatic castration-resistant prostate cancer. Given the high expression of B7-H3 in pediatric solid tumors, this target is emerging as a compelling therapeutic opportunity in pediatric oncology. Antitumor activity of vobra-duo was evaluated in pediatric solid tumor xenograft models, including Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, osteosarcoma, malignant rhabdoid tumor, hepatoblastoma, and Wilms tumor. Tumor-bearing mice received a single intraperitoneal dose of vobra-duo (6 mg/kg) or a matched control ADC (SYD988, anti-CD20 ADC with identical linker and payload). Tumor progression was defined as a fourfold increase in tumor volume. Event-free survival was analyzed using Kaplan-Meier methods, and responses were categorized as partial, complete, or maintained complete response. Vobra-duo induced objective responses across multiple tumor types, whereas the control ADC showed limited activity. No clear association was observed between B7-H3 protein expression and therapeutic response. These findings demonstrate broad preclinical efficacy of vobra-duo in pediatric solid tumors and support further clinical investigation of B7-H3-targeted therapies in children.
2026-03-13 | Trefoil Factor-3 Is a Hypoxia-Triggered Pro-Tumorigenic Factor in Hepatoblastoma.
Hepatoblastoma (HB) is the most common malignant liver tumour in children. Despite improved survival in low-risk disease, outcomes for advanced or relapsed HB remain poor, emphasising the need for new therapeutic targets. Hypoxia, a hallmark of aggressive tumours, has recently been implicated in HB pathogenesis, but the molecular mechanisms involved are unclear. This study aimed to characterise the hypoxia-driven transcriptomic landscape of HB and identify key mediators of tumour progression. Transcriptomic analyses of HB cell lines cultured under normoxic and hypoxic conditions were combined with bioinformatic interrogation of public HB datasets, immunohistochemistry of human and murine tumours and plasma ELISA assays. Functional roles of trefoil factor 3 (TFF3) were evaluated through overexpression and shRNA-mediated knockdown in vitro and in a β-catenin/YAP-driven mouse model of HB. Hypoxia induced broad transcriptional reprogramming in HB cells, including significant upregulation of TFF3, a secreted oncogenic peptide. TFF3 expression was elevated in HB tissues and plasma, and colocalized with hypoxia marker carbonic anhydrase 9 (CA9). TFF3 promoted proliferation, anchorage-independent growth and cisplatin resistance under both normoxia and hypoxia. Knockdown of murine Tff3 suppressed tumour formation and angiogenesis in vivo. Transcriptomic and molecular analyses revealed that TFF3 sustains C-MYC expression and modulates mTOR/GSK3β signalling. TFF3 is a hypoxia-inducible factor that enhances HB cell proliferation, survival and chemoresistance. Its tumour-promoting activity through C-MYC and mTOR pathways identifies TFF3 as a potential therapeutic target and circulating biomarker in hepatoblastoma.
2026-02-02 | Hepatoblastoma brain metastasis treated with stereotactic radiosurgery: Illustrative case and literature search.
Hepatoblastoma (HB) is the most prevalent pediatric liver malignancy, typically affecting children under 5 years of age. Although advances in multimodal therapy, including surgical resection and chemotherapy, have significantly improved survival rates, distant metastases, particularly to the lungs and the brain, remain a critical prognostic challenge. Brain metastases (BMs) from HB are exceedingly rare, with only a limited number of cases reported in the literature, and the management of these lesions is challenging. Stereotactic radiosurgery (SRS) is an increasingly popular treatment option for BM due to its ability to deliver high doses of radiation to the target volume with minimal exposure to surrounding normal tissues. In this paper, we present a rare case of HB with brain metastasis that was treated with SRS for the 1st time. The case was a 4-year-old male with a history of stage IV HB who was diagnosed with a single BM. Post-treatment magnetic resonance images following SRS revealed a reduction in lesion size on 6th-month follow-up imaging and then a stable lesion on further follow-up imaging. The case highlights the potential efficacy of SRS as a treatment option for BM from HB and supports its usage in the management of this complex condition. The progression-free survival was 17 months, and the overall survival was 84 months. SRS may represent a safe and effective treatment modality for HB BM, particularly in patients who are not suitable candidates for surgical resection or systemic therapy. Larger studies with extended follow-up are necessary to more accurately assess the long-term safety, efficacy, and clinical utility of SRS in the management of HB-related BM.
2025-11-01 | Myeloid derived suppressor cell depletion for the treatment of hepatoblastoma 4283
Abstract Description Introduction Hepatoblastoma (HB) is the most common form of liver cancer in childhood. Neutrophilic myeloid derived suppressor cells (PMN-MDSCs) are immunosuppressive cells recruited to liver tumors. Depletion of PMN-MDSCs has not been studied as immunotherapy for HB. Methods HB was induced in C57BL/6 or FVB/N mice using hydrodynamic tail vein injection of YAP and β-catenin plasmids. Anti-Ly6G, CXCR2 inhibitor (CXCR2i), and/or anti-PD1 were administered IP. Liver immune cells were isolated using density gradient centrifugation in Percoll. Results Anti-Ly6G administration caused a reduction in tumor weight, an increase in CD8+ T cells, an increase in the proliferation of CD8+T cells, and CD44+CD8+ activated T cells. Administering a combination of CXCR2i and anti-PD1 showed incomplete PMN-MDSC depletion, an increase in CD4+ T cells, an increase in activated CD44+CD4+ cells, and a decrease in frequency of naive CD4+CD62L+ cells, suggesting a helper T-cell driven antitumor response. Conclusion PMN-MDSC depletion has potential as a treatment for HB. We will further leverage this treatment strategy in combination with anti-PD1 checkpoint inhibition to assess its effect on HB. Funding Sources National Institute On Minority Health And Health Disparities of the National Institutes of Health under Award Number U54MD007601 (Ola HAWAII), The Chun Foundation, Andrew and Mary Weinberg Foundation Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
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Drug Discovery Landscape
7 orphan drug designations for Hepatoblastoma.
7 orphan drug designations for Hepatoblastoma.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
genetically engineered, replication-competent vesicular stomatitis virus (VSV)-based oncolytic viral therapy | other | FDA | — | Humane Genomics Inc. |
N-hydroxy-N-(methylacylfulvene)urea | small molecules | FDA | — | Lantern Pharma Inc. |
an autologous T-cell immunotherapy (ET140203) | cell therapies | FDA | Eureka Therapeutics, Inc. | |
[11C]Acetic Acid | small molecules | FDA | — | Advanced Imaging Projects, LLC |
Doxorubicin | small molecules | EMA | Double Bond Pharmaceutical AB | |
Iodine I 123 murine monoclonal antibody to alpha-fetoprotein | antibodies | FDA | — | Immunomedics, Inc. |
Iodine I 131 murine monoclonal antibody to alpha-fetoprotein | antibodies | FDA | — | Immunomedics, Inc. |
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