Hepatoblastoma (HB) is the most common pediatric primary liver tumor. About 20% of affected children have pulmonary metastasis at presentation. Survival rates for these children are dismal, not exceeding 25%. To study this subset of patients, we sequenced a metastatic HB cell line, HLM_2, and identified downregulation of the Liver X Receptor (LXR)/Retinoid X Receptor (RXR) pathway. LXR/RXRs function as transcriptional regulators that influence genes implicated in HB development, including the Wnt/β-catenin signaling pathway. We assessed the effects of a novel LXR/RXR agonist, UAB116, on metastatic HB, hypothesizing that this compound would affect genes governing the Wnt/β-catenin pathway, decreasing the metastatic phenotype of HLM_2 metastatic HB cells. We evaluated its effects on viability, proliferation, stemness, clonogenicity, and motility, and performed RNA sequencing to study differential gene regulation. Treatment with UAB116 for 72 h decreased HLM_2 proliferation, stemness, clonogenicity, and invasion. RNA sequencing identified an eight-fold increase in TRIM29, a gene known to inhibit β-catenin, in cells treated with UAB116. Administration of the LXR/RXR agonist, UAB116, reduces proliferation, stemness, and invasiveness of metastatic HB cells, potentially by upregulation of TRIM29, a known modulator of the Wnt/β-catenin pathway, providing support for further exploration of LXR/RXR agonism as a therapeutic strategy for metastatic HB.

The primary goal in the treatment of pediatric malignancies is to maintain effective cancer control while minimizing toxicities and late effects. Radiotherapy is a component of standard therapy against many pediatric cancers, but tumor cell DNA damage repair mechanisms and the hypoxic tumor microenvironment may limit the effectiveness of this modality. Additionally, irradiated cancer cells often acquire resistance to radiotherapy that permits cancer cell survival or stimulates tumor regrowth after treatment, further limiting the efficacy of radiotherapy. Various preclinical studies have investigated the potential of combining chemotherapy or immunotherapy with radiotherapy, with the goal of inducing a more lethal amount of DNA damage and prohibiting cells from acquiring radiotherapy resistance. This review provides an overview of the current strategies to enhance cancer cell response to radiotherapy, providing a framework to improve outcomes for children with solid tumors.

Hepatoblastoma is the predominant primary liver malignancy in children, and outcomes remain poor for patients with metastatic disease. Long non-coding RNAs (lncRNAs) regulate tumor behavior, but their role in metastatic hepatoblastoma is not well defined. This study investigates the expression and functional significance of the lncRNA, maternally expressed gene 3 (MEG3), in a metastatic hepatoblastoma model. RNA sequencing comparing the metastatic hepatoblastoma cell line, HLM_2, with its parental HuH6 cell line identified MEG3 as being significantly upregulated in metastatic cells. MEG3 expression was examined using hepatoblastoma patient datasets and validated using qPCR in cell lines, orthotopic tumors, and COA67 patient-derived xenografts. The effects of siRNA MEG3 knockdown in HLM_2 cells on clonogenicity, migration, and invasion were evaluated. The effects of MEG3 overexpression on migration and invasion were assessed in HuH6 cells. MEG3 was significantly upregulated in metastatic cells and orthotopic tumors compared with controls. MEG3 silencing reduced clonogenicity, tumorsphere formation, migration, and invasion. MEG3 overexpression increased migration and invasion. These findings indicate that MEG3 contributes to an aggressive tumor phenotype, highlighting the need for further examination into its mechanistic role in hepatoblastoma and its potential as a biomarker or therapeutic target.

Background/Objectives: Therapy-induced senescence (TIS), while initially growth-suppressive, may promote tumor recurrence through the persistence of senescent cells and the senescence-associated secretory phenotype (SASP). Topotecan, a topoisomerase inhibitor and a key component in the treatment of neuroblastoma (NBL), is known to lead to TIS. Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that has been linked to cellular senescence. PP2A is downregulated in NBL, primarily through upregulation of its endogenous inhibitors. We have previously shown that a novel small molecule, ATUX-1215, activates PP2A in NBL cells. Methods: The current study investigates the PP2A activator, ATUX-1215, as a senotherapeutic strategy in NBL. Results: We demonstrate that combining ATUX-1215 with topotecan leads to a reduction in senescent cell burden. Combination therapy suppressed PAI-1 and CCL2, key components of the SASP secretome, and enhanced apoptosis. PP2A activation reduced viability, stemness, and clonogenic survival post-TIS. In vivo, the combination of ATUX-1215 treatment with topotecan significantly delayed tumor growth and attenuated the pro-tumorigenic serum SASP. Conclusions: Our findings position PP2A activation as a senotherapeutic approach, transforming the tumor-promoting TIS program into a therapeutic vulnerability, offering a promising avenue to mitigate therapy resistance and improve outcomes in NBL.