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Single-cell analysis of hepatoblastoma identifies distinct tumor cell signatures that predict susceptibility to chemotherapy using patient-specific tumor spheroids

ABSTRACT: Method: In this study we use single cell RNA sequencing (scRNA-seq) to distinguish HB tumor cells from non-tumor cells and to identify distinct tumor cell types that account for the heterogeneity of HB. We also use a novel method to grow HB tumor cells as patient-specific spheroids (PDS) and show how this can be used to predict treatment response and identify novel therapeutic targets. Results: This study establishes that tumor heterogeneity can be defined by the relative proportions of five distinct subtypes of tumor cells. Notably, patient-derived HB spheroid cultures predict differential responses to treatment based on the transcriptomic signature of each tumor, suggesting a path forward for precision oncology for these tumors. Conclusions: These results define HB tumor heterogeneity with single-cell resolution and demonstrate that patient-derived spheroids can be used to evaluate responses to chemotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE186975 | GEO | 2022/03/01

REPOSITORIES: GEO

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Modeling Hepatoblastoma: Identification of Distinct Tumor Cell Populations and Key Genetic Mechanisms through Single Cell Sequencing (bulk)

Project description:Hepatoblastoma (HB) is the most common primary liver malignancy of childhood. However, molecular investigations of the disease are limited and effective treatment options are lacking. The use of patient derived xenografts (PDX) to study biology and treatment strategies of HB has proven to be a useful tool. There is currently a knowledge gap in the investigation of key driver cells of HB in PDX models. Key driving pathways of HB tumor including WNT, AP-1, Hedgehog, Notch and MAPK pathways and genes such as GPC3, DLK1 and HMGA2 have been identified in primary HB tumor and PDX as integral players in HB tumor growth. Cell clusters have been defined with distinct roles in tumor development. Cell populations with initiating, angiogenic (endothelial), maintenance, and progression signatures have been identified in one HB patient tumor and corresponding PDX tumor. Critical pathways combined with identification of distinct cell populations within HB tumor will allow for investigation of novel treatment strategies in vitro and in vivo.

2021-07-29 | GSE180664 | 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

Modeling Hepatoblastoma: Identification of Distinct Tumor Cell Populations and Key Genetic Mechanisms through Single Cell Sequencing (scRNA-seq)

2021-07-29 | GSE180665 | GEO

A Developmentally Prometastatic Niche in Neonatal Liver to Hepatoblastoma mediated by Cxcl1/Cxcr2 Axis

Project description:We find that various HB cell lines including HepG2 cells are consistently and considerably more tumorigenic and metastatic in the P5Tx model than in the P60Tx models. Sc-RNAseq of the P5Tx and P60Tx HepG2 models reveals that the P5Tx tumor is more hypoxic and has more activated hepatic stellate cells (aHSCs) in the tumor-surrounding liver which express significantly higher levels of Cxcl1 than those from the P60Tx model. We find these differences are developmentally present in the normal P5 and P60 liver. We show that Cxcl1/Cxcr2 axis mediates HB cell migration and is critical to HB cell survival under hypoxia. Treating HepG2 P60Tx model with recombinant CXCL1 protein induces multifocal intrahepatic and pulmonary metastasis and CXCR2 knockout in HepG2 cells abolishes their metastatic potential in the P5Tx model. Lastly, we show that in metastatic HB patient tumors there is a similar larger population of aHSCs in the tumor-surrounding liver than the localized tumors, and tumor hypoxia is significantly associated with HB patient prognosis.

2022-04-01 | GSE186335 | GEO

Single-cell analysis of hepatoblastoma identifies distinct tumor cell signatures that predict susceptibility to chemotherapy using patient-specific tumor spheroids

Project description:Single-cell analysis of hepatoblastoma identifies distinct tumor cell signatures that predict susceptibility to chemotherapy using patient-specific tumor spheroids

| PRJNA777110 | ENA

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

Project description: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.

2020-07-14 | GSE146548 | GEO

Genomic Copy-Number Variations in Hepatoblastoma Patients Revealed by Array Comparative Genomic Hybridization

Project description:Purpose: Hepatoblastoma (HB) is a malignant pediatric hepatic progenitor cell tumor with uncertain etiology. To discover genomic biomarkers associated with this malignancy, we conduct the study. Experimental Design: A panel of ten cases and two pairs of identical twins for HB were screened using high-resolution array-based comparative genomic hybridization (array CGH) technology. Genomic DNA from the peripheral blood was subject to our laboratory investigation. Results: In total of the twelve HB cases tested, we identified four high recurrent copy-number variations (CNVs) including gain on 1p13.3 (25%) and losses on 5p15.33 (33.3%), 16q12.2 (33.3%), and 19q13.42 (25%). Additionally, the twin study indicated that microdeletions of 3p12.1 and 12p13.2 correlated with hepatoblastoma occurrence. Among these candidate CNVs, 5p15.33 and 16q12.2 not only the most prevalent genomic deletion in this survey, but also encompassed hepatic expressed gene, Zinc finger, DHHC-type containing 11B (ZDHHC11B) and Zinc finger, DHHC-type containing 11 (ZDHHC11) map to 5p15.33; carboxylesterase 4-like (CES4) map to 16q12.2. Furthermore, the microdeletion of 5p15.33 was associated with high mortality rate (3/3; P = 0.018) in patients with native liver. Currently, the only surviving patient with 5p15.33 microdeletion is who has receipt liver transplantation. Conclusions: These results suggested that losses on 3p12.1, 5p15.33, 12p13.2 and 16q12.2 may be pathogenic for HB. In addition, HB patient who affected by 5p15.33 microdeletion seems to carry high risk of mortality unless undergo liver transplantation. Thus, 5p15.33 microdeletion was suggested as potential prognostic biomarker for poor survival in hepatoblastoma.

2010-10-01 | GSE18408 | 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

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

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

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