The origin of hepatocellular carcinoma is regulated by metabolic zonation [Single Nuclear Genotyping]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE309044 | GEO | 2025/11/10
REPOSITORIES: GEO
Similar Datasets
Project description:The origin of cancer is poorly understood because premalignant cells are rarely followed in their native environments. While the spatial compartmentalization of metabolic functions is critical for proper liver function, it is unknown if cancers arise from some zones but not others, and if there are metabolic determinants of cancer risk. Zone-specific, mosaic introduction of Ctnnb1 and Arid2 mutations, commonly co-mutated genes in hepatocellular carcinoma (HCC), showed that position and metabolic context determine clone fates. Ctnnb1/Arid2-driven cancers were much more likely to arise in zone 3. The zone 3 genes Gstm2 and Gstm3 were required for efficient HCC initiation, in part through inhibition of ferroptosis. In the liver, the zonal determinants of HCC development can reveal metabolic vulnerabilities of cancer.
2025-11-10 | GSE308959 | GEO
Project description:The origin of cancer is poorly understood because premalignant cells are rarely followed in their native environments. While the spatial compartmentalization of metabolic functions is critical for proper liver function, it is unknown if cancers arise from some zones but not others, and if there are metabolic determinants of cancer risk. Zone-specific, mosaic introduction of Ctnnb1 and Arid2 mutations, commonly co-mutated genes in hepatocellular carcinoma (HCC), showed that position and metabolic context determine clone fates. Ctnnb1/Arid2-driven cancers were much more likely to arise in zone 3. The zone 3 genes Gstm2 and Gstm3 were required for efficient HCC initiation, in part through inhibition of ferroptosis. In the liver, the zonal determinants of HCC development can reveal metabolic vulnerabilities of cancer.
2025-11-10 | GSE308568 | GEO
Project description:Background & Aims: Recent genomic studies have identified frequent mutations of AT-rich interactive domain 2 (ARID2) in hepatocellular carcinoma (HCC), but it is not still understood how ARID2 exhibits tumor suppressor activities. Methods: We established the ARID2 knockout HCC cell lines by using CRISPR/Cas9 system, and investigated the gene expression profiles and biological functions. Results: Bioinformatic analysis indicated that UV-response genes were negatively regulated in the ARID2-KO cells, and they were certainly sensitized to UV irradiation. ARID2 depletion attenuated nucleotide excision repair (NER) of DNA damage sites introduced by exposure to UV as well as chemical compounds known as carcinogens for HCC, benzo[a]pyrene and FeCl3, since XPG could not be accumulated without ARID2. By using large-scale public data sets, we validated that ARID2 knockout could lead to similar molecular changes between in vitro and in vivo, and moreover observed a higher number of somatic mutations in the ARID2-mutated subtypes than that in the ARID2 wild-type across various types of cancers including HCC. Conclusions: We provided evidence that ARID2 knockout could contribute to disruption of NER process through inhibiting the recruitment of XPG, resulting in susceptibility to carcinogens and potential hypermutation. These findings have far-reaching implications for therapeutic targets in cancers harboring ARID2 mutations.
2020-01-22 | GSE144021 | GEO
Project description:We analyzed 801 primary HCC developed in 720 patients. Samples were collected from 1992 to 2016 in three French tertiary liver centers in patients treated by liver resection, liver transplantation (surgical samples) and in patients treated by radiofrequency ablation and with advanced HCC treated by non-curative therapies (tumor biopsies). All samples obtained from surgical samples or tumor biopsy were immediately frozen in liquid nitrogen and stored at -80°C prior extraction. We assessed mRNA expression by quantitative RT-PCR in a subset of 757 liver tumor samples. 517 to 782 HCC, according to the gene considered, were sequenced for 30 driver genes (TERT, TP53, CTNNB1, AXIN1, PIK3CA, ARID1A, ARID2, RPS6KA3, NFE2L2, CDKN2A, IL6ST, BRAF, STAT3, HNF1A, JAK1, KRAS, GNAS, KEAP1, IRF2, HRAS, NRAS, TSC2, APOB, TSC1, ALB, CDKN1A, MAP1B, SETD2, ATM and MLL2).
2019-04-05 | GSE129322 | GEO
Project description:Background: The tumor microenvironment can be classified into immunologically active “inflamed” tumors and inactive “non-inflamed” tumors based on the infiltration of cytotoxic immune cells. Previous studies on liver cancer have reported a superior prognosis for inflamed tumors compared to non-inflamed tumors. However, liver cancer is highly heterogeneous immunologically and genetically, and a finer classification of the liver cancer microenvironment may improve our understanding of its immunological diversity and response to immune therapy. Methods: We characterized the immune gene signatures of 234 primary liver cancers, mainly virus-related, from a Japanese population using RNA-Seq of tumors and matched non-tumorous hepatitis livers. We then compared them with the somatic alterations detected using the whole-genome sequencing. Findings: Liver cancers expressed lower levels of immune marker genes than non-tumorous hepatitis livers, indicating immunosuppression in the tumor microenvironment. Several immunosuppression mechanisms functioned actively and mutually exclusively, resulting in four immune subclasses of liver cancer: tumor-associated macrophage (TAM), CTNNB1, cytolytic activity (CYT), and regulatory T cell (Treg). The CYT and Treg subclasses represented inflamed tumors, while the TAM and CTNNB1 subclasses represented non-inflamed tumors. The TAM subclass, which comprised 31% of liver cancers, showed a poor survival, expressed elevated levels of extracellular matrix genes, and was associated with somatic mutations of chromatin regulator ARID2. The results of cell line experiments suggested a functional link between ARID2 and chemokine production by liver cancer cells. Interpretation: Primary liver cancer was classified into four subclasses based on mutually exclusive mechanisms for immunosuppression. This classification indicate the importance of immunosuppression mechanisms, such as TAM and Treg, as therapeutic targets for liver cancer.
2020-01-21 | GSE143941 | GEO
Project description:Background & Aims CTNNB1-mutated HCCs exhibit a relatively low stem-like and well-differentiated phenotype. However, the mechanism remains unclear. Ripply transcriptional repressor 1 (RIPPLY1), a transcriptional repressor required for somite segmentation, has hardly been studied in cancer. Here, we aim to unveil the role of RIPPLY1 in the regulation of cancer cell stemness in CTNNB1-mutated HCCs. Approach and Results RIPPLY1 was found to be transactivated by the Wnt/β-Catenin signal pathway. Human sample analysis confirmed that RIPPLY1 was significantly upregulated in CTNNB1-mutated HCC tissues and positively correlated with better prognosis of HCC patients. Hepatocyte-specific deletion of RIPPLY1 promoted tumorigenesis and progression in DEN/PB-induced CTNNB1-mutated HCC mouse model and hydrodynamic tail-vein injection (HDTVi)-induced CTNNB1-mutated HCC mouse model. RIPPLY1 knockout tumor cells displayed upregulated levels of stem cell makers and enhanced cancer stem cell properties. Co-IP and MS identified TBX19 as the target protein of RIPPLY1. RIPPLY1 suppressed the transcriptional activity of TBX19 via recruiting TLE1 and promoting proteasome-dependent degradation of TBX19. TBX19 deficiency abolished the effect of RIPPLY1 loss on cancer cell stemness in CTNNB1-mutated HCCs. Conclusion： Loss of RIPPLY1 promotes cancer cell stemness via facilitating the TBX19 transcriptional activity in CTNNB1-mutated HCCs.
2025-09-19 | GSE300485 | 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:First-line immune checkpoint inhibitor (ICI) combinations have shown responses in subsets of patients with advanced hepatocellular carcinoma (HCC). Nearly half of patients are Wnt active with mutations in CTNNB1 (encoding for beta-catenin), AXIN1/2, or APC, and demonstrate limited benefit to ICI due to an immunosuppressive tumor microenvironment. We investigated a novel siRNA encapsulated in lipid nanoparticle targeting CTNNB1 (LNP-CTNNB1) in multiple beta-catenin-mutated immunocompetent HCC mouse models, observing complete response. Integrated single-cell and spatial transcriptomics revealed complete cellular and zonal reprogramming of CTNNB1-mutated tumors, and a spatiotemporal shift in innate immune surveillance with intra-tumoral pro-inflammatory myeloid infiltration following LNP-CTNNB1 intervention. beta-catenin knockdown initiated tumor cell-intrinsic type I/II interferon signaling accompanied by IRF2 upregulation, which was suppressed in CTNNB1-mutated HCCs. IRF2 re-expression in beta-catenin-mutated HCC restored adaptive tumor immunity with increased CD4+ T cells and impaired recruitment of resident T regulatory cells. Finally, LNP-CTNNB1 synergized with ICI in advanced-stage disease through increasing intra-tumoral recruitment of cytotoxic T cells. In summary, RNAi-mediated inhibition of CTNNB1 is efficacious as monotherapy and in combination with ICI in CTNNB1-mutated HCCs through remodeling both tumor cell intrinsic signaling and global immune surveillance, thus providing rationale for clinical investigations.
2025-05-02 | GSE290449 | GEO
Project description:First-line immune checkpoint inhibitor (ICI) combinations have shown responses in subsets of patients with advanced hepatocellular carcinoma (HCC). Nearly half of patients are Wnt active with mutations in CTNNB1 (encoding for beta-catenin), AXIN1/2, or APC, and demonstrate limited benefit to ICI due to an immunosuppressive tumor microenvironment. We investigated a novel siRNA encapsulated in lipid nanoparticle targeting CTNNB1 (LNP-CTNNB1) in multiple beta-catenin-mutated immunocompetent HCC mouse models, observing complete response. Integrated single-cell and spatial transcriptomics revealed complete cellular and zonal reprogramming of CTNNB1-mutated tumors, and a spatiotemporal shift in innate immune surveillance with intra-tumoral pro-inflammatory myeloid infiltration following LNP-CTNNB1 intervention. beta-catenin knockdown initiated tumor cell-intrinsic type I/II interferon signaling accompanied by IRF2 upregulation, which was suppressed in CTNNB1-mutated HCCs. IRF2 re-expression in beta-catenin-mutated HCC restored adaptive tumor immunity with increased CD4+ T cells and impaired recruitment of resident T regulatory cells. Finally, LNP-CTNNB1 synergized with ICI in advanced-stage disease through increasing intra-tumoral recruitment of cytotoxic T cells. In summary, RNAi-mediated inhibition of CTNNB1 is efficacious as monotherapy and in combination with ICI in CTNNB1-mutated HCCs through remodeling both tumor cell intrinsic signaling and global immune surveillance, thus providing rationale for clinical investigations.
2025-05-02 | GSE290445 | GEO
Project description:First-line immune checkpoint inhibitor (ICI) combinations have shown responses in subsets of patients with advanced hepatocellular carcinoma (HCC). Nearly half of patients are Wnt active with mutations in CTNNB1 (encoding for beta-catenin), AXIN1/2, or APC, and demonstrate limited benefit to ICI due to an immunosuppressive tumor microenvironment. We investigated a novel siRNA encapsulated in lipid nanoparticle targeting CTNNB1 (LNP-CTNNB1) in multiple beta-catenin-mutated immunocompetent HCC mouse models, observing complete response. Integrated single-cell and spatial transcriptomics revealed complete cellular and zonal reprogramming of CTNNB1-mutated tumors, and a spatiotemporal shift in innate immune surveillance with intra-tumoral pro-inflammatory myeloid infiltration following LNP-CTNNB1 intervention. beta-catenin knockdown initiated tumor cell-intrinsic type I/II interferon signaling accompanied by IRF2 upregulation, which was suppressed in CTNNB1-mutated HCCs. IRF2 re-expression in beta-catenin-mutated HCC restored adaptive tumor immunity with increased CD4+ T cells and impaired recruitment of resident T regulatory cells. Finally, LNP-CTNNB1 synergized with ICI in advanced-stage disease through increasing intra-tumoral recruitment of cytotoxic T cells. In summary, RNAi-mediated inhibition of CTNNB1 is efficacious as monotherapy and in combination with ICI in CTNNB1-mutated HCCs through remodeling both tumor cell intrinsic signaling and global immune surveillance, thus providing rationale for clinical investigations.
2025-05-02 | GSE290444 | GEO