A novel kinase inhibitor for b-catenin mutant hepatocellular carcinoma [Cut&Run]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE213515 | GEO | 2023/05/03
REPOSITORIES: GEO
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Project description:We screened HCC organoids to identify a CTNNB1-mutant HCC selective small molecule (WNTinib), with MOA depending on reactivation of cytoplasmic EZH2, leading to its nuclear translocation and selective transcriptional block of WNT targets We then performed gene expression profiling analysis using data obtained from RNA-seq of 2 genetically different organoids at 3 time points.
2023-05-03 | GSE213517 | GEO
Project description:CTNNB1 is the most frequently mutated gene in hepatocellular carcinoma (HCC). However, its clinical relevance remains controversial. We determined an evolutionarily conserved β-catenin signature by comparative analysis of gene expression data from human HCC and a mouse model (GSE43628). We generated gene expression data from the tumors of 88 HCC patients who underwent surgical resection as the primary treatment. We used these gene expression data to develop a new prognostification model for prognosis of HCC after surgery. We generated gene expression data from the tumors of 88 HCC patients who underwent surgical resection as the primary treatment.
2015-05-21 | E-GEOD-43619 | biostudies-arrayexpress
Project description:CTNNB1 is the most frequently mutated gene in hepatocellular carcinoma (HCC). However, its clinical relevance remains controversial. We determined an evolutionarily conserved β-catenin signature by comparative analysis of gene expression data from human HCC (GSE43619) and a mouse model.
2014-12-31 | GSE43628 | GEO
Project description:Background & Aims: Patients with beta-catenin (encoded by CTNNB1)-mutated hepatocellular carcinoma (HCC) have demonstrated limited clinical benefit to first-line immunotherapy (IO). Animal models of HCC expressing mutant-beta-catenin and additional aberrations via hydrodynamic tail vein injection with sleeping beauty transposon/transposase (SB-HDTVI) represent clinically relevant human HCC subsets. Here, we perform transcriptomic analysis on multiple beta-catenin-mutated and non-mutated HCC animal models to identify Mutated beta-catenin Gene Signature (MBGS) for HCC patient stratification for CTNNB1-mutations and IO response. Methods: We co-expressed in mice mutant-NFE2L2 and hMET +- mutant-CTNNB1 via SB-HDTVI and monitored for HCC development. Bulk RNA-sequencing was assessed for transcriptional differences between various beta-catenin-mutated and non-mutated models. MBGS was generated for predictive ability of CTNNB1 mutations and IO resistance in multiple HCC patient cohorts. Results: Co-expression of S45Y-beta-catenin + G31A-NFE2L2 + hMet (beta-N-M) resulted in HCC development by 4.5 weeks while co-expression of G31A-NFE2L2 + hMet (N-M) led to HCC by 14 weeks with tumors being positive for expected targets by immunohistochemistry (IHC). Bulk RNA-sequencing comparing beta-catenin-driven versus non-beta-catenin driven models yielded 95 common upregulated genes. Differential gene expression analysis of the common genes comparing CTNNB1-mutated vs non-mutated TCGA patients narrowed the gene panel to 13-(or 10-) genes. This MBGS predicted CTNNB1-mutation status in TCGA (n=374) and French (n=398) patient cohorts (with ROC AUC of 0.90 and 0.94). High MBGS expression was also associated with no overall and progression-free survival benefit when comparing atezolizumab + bevacizumab versus sorafenib arms in IMbrave150 cohort implying fewer treatment effects. Conclusions: In an era of patient molecular stratification for HCC, MBGS may aid in optimally selecting patients for IO through diagnosis of a molecular subset which lacks optimal response.
2024-10-09 | GSE261316 | GEO
Project description:CTNNB1 is the most frequently mutated gene in hepatocellular carcinoma (HCC). However, its clinical relevance remains controversial. We determined an evolutionarily conserved β-catenin signature by comparative analysis of gene expression data from human HCC and a mouse model (GSE43628). We generated gene expression data from the tumors of 88 HCC patients who underwent surgical resection as the primary treatment. We used these gene expression data to develop a new prognostification model for prognosis of HCC after surgery.
2015-05-21 | GSE43619 | GEO
Project description:We study the role of CTNNB1 in immune escape in HCC.
2019-06-13 | GSE125336 | GEO
Project description:We report transcritomic characterization of changes in CTNNB1 mutation positive HCCs in comparison to paratumoral tissues 4 pair of HCC and paratumoral liver tissues are sequenced and compared
2014-08-15 | E-GEOD-55048 | biostudies-arrayexpress
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
Project description:Multi-omics approaches were utilized to comprehensively analyze the molecular characteristics of hepatocellular carcinoma (HCC) in South Texas (STX) Hispanics. Exome sequencing revealed high mutation frequencies of AXIN2 and CTNNB1, suggesting a predominant activation of the Wnt/beta-catenin pathway. Cell cycles were positively-, and liver functions were negatively-enriched on gene set enrichment analysis of our transcriptomic and proteomic datasets. Enrichments of gene sets representing specific liver metabolic pathways were found to be associated with the dysregulation of corresponding metabolites. Significant reduction of the majority of lipids seen in serum samples of HCC patients and many fatty acids in HCC tumors corroborate negative adipogenesis and lipid metabolism enrichments. We identified two subtypes of HCC using enrichment scores from paired tumor-nontumor samples of STX-Hispanics or TCGA-LIHC. The subtype with better overall survival revealed pronounced positive enrichments of immune-, angiogenesis-, and negative enrichments of liver function-related hallmark gene sets than the other. The former had higher levels of immune checkpoint and immune exhaustion markers. Together, we report molecular features of HCC, specific and non-specific to Hispanics.
2023-07-11 | MSV000092403 | MassIVE
Project description:Hepatocellular adenomas (HCA) are rare benign tumours of the liver which have been extensively classified at the clinico-pathological, genetic and proteomic levels. The b-HCA subtype has several types of mutations in the ß-catenin gene (CTNNB1) with very different clinical phenotypes and risks. Recently, we revealed a glutamine synthetase (GS) positive rim in b-HCA exon 3 S45 and b-HCA exon 7/8, indicating protein expression heterogeneity into b-HCA in comparison with the rest of the tumor. A difference in vascularization had been associated with this rim revealed by a diffuse CD34 labeling only at the center of the tumor and not in the rim. In this study, we sought to characterize this tumor heterogeneity in a tumor considered monoclonal. We used laser microdissection to analyze the rim (R) at the molecular level. We cut 1mm² areas of GS+/CD34- rim on serial cuts and we analyzed in parallel, the mutation status of CTNNB1 and the levels of protein expression by mass spectrometry. Comparison of the proteomic profiles of the rim versus the tumor center (T) revealed a sufficiently large protein expression differential to distinguish them by principal component analysis. Forty proteins were significantly differentially expressed between R and T, including a large majority of amino acid and lipid metabolism proteins whose deregulations were comparable to a perivenous expression profile in a normal hepatocyte context. Our results suggest that protein expression in the rim seems not to be dependent on the mutational status of CTNNB1 but rather on the influence of venous drainage. Thanks to laser microdissection coupled with proteomic analysis on fixed tissue, we were able to analyze this tumor heterogeneity and provide elements of biological interpretation.
2023-05-02 | PXD031323 | Pride