Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Inhibiting YAP1 in hepatoblastoma drives therapeutic differentiation of tumor cells to functional hepatocyte-like cells

ABSTRACT: Despite advances in surgical care and chemotherapeutic regimens, the five-year survival rate for Stage IV Hepatoblastoma (HB), the predominant pediatric liver tumor, remains at 27%. YAP1 and β-Catenin co-activation occur in 80% of children’s HB; however, a lack of conditional genetic models precludes exploration of tumor maintenance and therapeutic targets. Thus, the clinical need for a targeted therapy remains unmet. Given the predominance of YAP1 and β-catenin activation in children’s tumors, we sought to evaluate YAP1 as a therapeutic target in HB. We engineered the first conditional murine model of HB using hydrodynamic injection to deliver transposon plasmids encoding inducible YAP1S127A, constitutive β-CateninDelN90, and a luciferase reporter to murine liver. Tumor regression was evaluated using in vivo bioluminescent imaging, and tumor landscape characterized using RNA sequencing, ATAC sequencing and DNA foot-printing. Here we show that YAP1 inhibition mediates >90% tumor regression with survival for 230+ days in mice. Mechanistically, YAP1 inhibition induces a cell fate switch driving therapeutic differentiation of HB tumors into Ki-67 negative “hbHep cells” with hepatocyte-like morphology and mature hepatocyte gene expression.

ORGANISM(S): Mus musculus

PROVIDER: GSE146548 | GEO | 2020/07/14

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Microarray expression data from FVB mice with induced hepatoblastoma (liver tumors)

Project description:Hepatoblastoma (HB) is the most common pediatric liver tumor, and there are no targeted therapies available for children with HB. We have previously developed a murine model of HB which is driven by coactivation of the oncogenes YAP1 and β-catenin (CTNNB1) [Tao J, Calvisi D, Ranganathan S, et al. Gastroenterology, 2014 Sep; 147(3): 690–701]. We used the Sleeping Beauty transposase system combined with hydrodynamic tail vein injection to deliver plasmids containing mutant activated forms of YAP1 (YAP S127A) and β-catenin (ΔN90 β-catenin) to a small number of pericentral hepatocytes. We have shown that these few transformed hepatocytes proliferate and dedifferentiate, eventually forming histologically heterogeneous tumors that resemble various subtypes of human HB (which is also highly heterogeneous), including areas of well-differentiated fetal, crowded fetal, embryonal, and blastemal HB. Our goal was to investigate how coactivation of YAP1 and β-catenin drive the dedifferentiation of hepatocytes into hepatoblast-like tumor cells over time, leading to HB tumors. In order to measure changes in gene expression during tumorigenesis in our model, we used an Affymetrix microarray to analyze isolated RNA from wild type FVB mouse livers and tissue from livers laden with late-stage HB tumors.

2018-03-30 | GSE112485 | GEO

GREB1, a novel target of Wnt signaling, promotes development of hepatoblastoma by suppressing TGFβ signaling

Project description:The β-catenin mutation is frequently observed in hepatoblastoma (HB), but the underlying mechanism by which Wnt/β-catenin signaling induces HB tumor formation is unknown. We found that expression of growth regulation by estrogen in breast cancer 1 (GREB1) depends on Wnt/β-catenin signaling in HB patients. GREB1 was localized to the nucleus where it bound Smad2/3 in a competitive manner with p300 and inhibited TGFβ signaling, thereby promoting HepG2 HB cell proliferation. Forced expression of β-catenin, YAP, and c-Met induced HB-like mouse liver tumor (BYM mice), with an increase in GREB1 expression and HB markers. Depletion of GREB1 strongly suppressed marker gene expression and HB-like liver tumorigenesis, and instead enhanced TGFβ signaling in BYM mice. Furthermore, antisense oligonucleotides for GREB1 suppressed the formation of HepG2 cell-induced tumors and HB-like tumors in vivo. We propose that GREB1 is a novel target molecule of Wnt/β-catenin signaling and required for HB progression.

2019-07-18 | GSE133976 | GEO

Mouse hepatoblastoma models with expression of mutant β-catenin and/or c-Myc for therapeutic target identification of childhood liver cancer

Project description:Hepatoblastoma (HB), the most common type of pediatric liver cancer, is associated with aberrant wnt/β-catenin activation and Myc amplification/overexpression. Mice expressing both alleles developed HBs and HCCs with incomplete penetrance by 5-6 weeks of age with fetal and mixed fetal/embryonal HBs, the most prevalent histologic HB subtypes seen in children being the predominant tumor types. To address the roles of mutant wnt/β-catenin activation and Myc over-expression in the pathogenesis of HB, c-Myc and mutant dominant-stable β-catenin were co-targeted to immature cells of the developing mouse liver.

2017-08-23 | GSE79084 | GEO

EZH2 is a key component of Hepatoblastoma tumor cell growth

Project description:To understand molecular mechanisms driving HB pathogenesis, we hypothesize that pathologic activation of Enhancer of Zeste Homolog 2 contributes to hepatoblastoma propagation. Here we demonstrate that EZH2 promotes proliferation in HB cell lines through interaction with β-catenin, the most frequently mutated gene in HB. We demonstrate that canonical and noncanonical EZH2 signaling occur in HB tumor cells, likely driven by aberrant EZH2 expression. We use comparison groups of liver cancer, hepatocytes, and dermal fibroblasts to establish the hepatoblastoma identity of our patient-derived cell lines.

2023-11-15 | GSE235202 | GEO

Developmental vascular regression is regulated by a Wnt/b-catenin, MYC, P21 (CDKN1A) pathway that controls cell proliferation and cell death

Project description:Normal development requires tight regulation of cell proliferation and cell death. Here, we investigated these control mechanisms in the hyaloid vessels, a temporary vascular network in the mammalian eye that requires a Wnt/β-catenin response for scheduled regression. Transcriptome analysis of the postnatal day 5 mouse hyaloid showed expression of several Wnt pathway proteins. We investigated whether the hyaloid Wnt response was linked to the oncogene Myc, and the cyclin-dependent kinase inhibitor P21 (CDKN1A), both established regulators of cell cycle progression and cell death. Our analysis showed that the Wnt pathway coreceptors LRP5 and LRP6 have overlapping activities mediating the Wnt/β-catenin signaling in hyaloid vascular endothelial cells (VECs). We also showed that both Myc and Cdkn1a are downstream of the Wnt response and are required for hyaloid regression but for different reasons. Conditional deletion of Myc in VECs suppressed both proliferation and cell death. By contrast, conditional deletion of Cdkn1a resulted in VEC over-proliferation that countered the effects of cell death on regression. When combined with analysis of MYC, and P21 protein levels, this analysis suggests that a Wnt/β-catenin, MYC-P21 pathway regulates scheduled hyaloid vessel regression.

2018-06-15 | GSE113294 | GEO

Zebrafish liver: Tg(fabp10a:pt-beta-catenin) versus non-transgenic control siblings

Project description:To investigate mechanisms by which activated β-catenin signaling promotes liver tumor formation and to identify potential therapeutics for these cancers, we generated transgenic zebrafish expressing hepatocyte-specific activated β-catenin (Tg(fabp10a:pt-β-cat) zebrafish. As adults, these animals show increased liver size, decreased survival, and histologic abnormalities similar to human HCC. To further characterize our model, we used microarray analysis to compare gene expression in Tg(fabp10a:pt-β-cat) zebrafish livers to that of non-transgenic control sibling livers. This experiment includes 2 biological replicates. Each replicate represents one Tg(fabp10a:pt-beta-catenin) zebrafish compared to non-transgenic control sibling.

2015-04-30 | E-GEOD-68124 | biostudies-arrayexpress

β-Catenin mutations as determinants of hepatoblastoma phenotypes in mice

Project description:Hepatoblastoma (HB) is the most common pediatric liver cancer. While long-term survival is generally favorable, it is dependent upon clinical stage, tumor histology and a variety of biochemical and molecular features. HB appears almost exclusively before the age of three years, is represented by seven histologic subtypes and is usually associated with highly heterogeneous somatic mutations in the CTNNB1 gene, which encodes b-catenin, a Wnt ligand-responsive transcriptional co-factor. Numerous recurrent b-catenin mutations, not previously documented in HB, have also been identified in various other pediatric and adult cancer types. Little is known regarding the underlying factors that determine the above HB features and behaviors or whether non-HB-associated b-catenin mutations are tumorigenic when expressed in hepatocytes. Here, we investigated the oncogenic properties of 14 different HB- and non-HB-associated b-catenin mutants encoded by Sleeping Beauty vectors following their delivery into the liver by hydrodynamic tail vein injection. We show that all b-catenin mutations, as well as wild-type b-catenin are tumorigenic when co-expressed with a mutant form of yes-associated protein. However, tumor growth rates, histologies, nuclear:cytoplasmic partitioning and metabolic and transcriptional landscapes were strongly influenced by the identities of the b-catenin mutations. These findings provide a context for understanding at the molecular level the notable biological diversity of this important pediatric cancer.

2019-10-09 | GSE130178 | GEO

Transcription profiling of liver from wild type and tumor suppressor Apc knock-out mice

Project description:A "Cartes d'Identite des Tumeurs" (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net). This work aims to demonstrate a key role for the Wnt/beta-catenin pathway in liver embryonic growth and in controlling the fate of hepatoblasts, preventing them to differentiate towards the hepatocyte lineage, and guiding them to a duct morphogenesis. Through the inactivation of Apc (adenomatous Polyposis Coli) tumor suppressor gene in hepatoblasts by a Cre-loxP strategy, the ectopic activation of beta-catenin targeted in hepatoblasts after liver bud formation leads to a lethal embryonic phenotype, characterized by liver hypoplasia, a blockade of hepatocyte differentiation and commitment to a biliary fate. (this work was supported by INSERM and the B^SLigue Nationale

2007-08-07 | E-TABM-295 | biostudies-arrayexpress

β-catenin deficiency in hepatocytes promotes liver tumorigenesis driven by oncogenic β-Catenin and c-Met in mice

Project description:To understand differential gene expression globally with/without hepatocyte β-catenin knockout on liver cancer mouse model, RNA-seq analysis were examined using hydrodynamic β-catenin and c-Met induced β-catenin∆H (β-cateninF/F:Alb-cre) and WT mice.

2017-04-25 | GSE97914 | GEO

Hepatic stellate cell-derived oxylipin activates leukotrine B4 receptor 2-β-catenin-YAP1 cascade to promote liver tumorigenesis

Project description:Hepatocellular carcinoma (HCC) is the 3rd most deadly malignancy due to limited therapeutic options. Activated hepatic stellate cells (aHSC) give rise to major cancer-associated myofibroblasts in HCC and considered a potential therapeutic target. Here we report that selective ablation of stearoyl CoA desaturase (Scd) in aHSC globally suppressed nuclear β-catenin (CTNNB1) and YAP1 in the tumor microenvironment and prevented liver tumorigenesis in mice. Tumor suppression was associated with reduced leukotriene B4 receptor 2 (LTB4R2) and its high affinity oxylipin ligand, 12-hydroxyheptadecatrienoic acid (12-HHTrE). LTB4R2 ablation and pharmacological inhibition, recapitulated CTNNB1 and YAP1 inactivation and tumor suppression in vivo and in culture. Single cell RNA sequencing identified a unique subset of tumor-associated aHSC expressing Cyp1b1 but no other 12-HHTrE biosynthetic genes. aHSC released 12-HHTrE in a manner dependent on SCD and their conditioned medium reproduced the LTB4R2-mediated tumor-promoting effects of 12-HHTrE in HCC cells. CYP1B1-expressing aHSC were detected in proximity of LTB4R2-positive cancer cells in human HCC and the growth of patient HCC organoids was blunted by LTB4R2 antagonism or knockdown. Collectively, our research identified a novel aHSC-initiated 12-HHTrE-LTB4R2-CTNNB-YAP1 pathway as a potential HCC therapeutic target.

2023-03-13 | GSE193980 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data