Single-cell transcriptome reveals the reprogramming of immune microenvironment during the transition from MASH to HCC
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ABSTRACT:
PROVIDER: PRJNA1189505 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR31446778_1.fastq.gz | Fastqsanger.gz | |||
| SRR31446778_2.fastq.gz | Fastqsanger.gz |
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Project description:Metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC) development is accompanied by the accumulation of immune cells within the hepatic microenvironment, yet its immunological networks remain obscure. Herein, we illustrate the profound reprogramming of the liver immune microenvironment during the transition from MASH to HCC by single-cell RNA sequencing (scRNA-seq).
2025-06-18 | GSE282630 | GEO
Project description:To determine the role of the hepatic microenvironment in HCC metastasis, we compared the gene expression profiles of 20 noncancerous surrounding hepatic tissues from two HCC patient groups, those with primary HCC together with venous metastasis which we termed a metastasis-inclined microenvironment (MIM) and those with HCC without detectable metastasis, which we termed a metastasis-averse microenvironment (MAM). There were a total of 20 cDNA microarrays performed, comparing 9 MIM or 11 MAM HCC patient samples to a common reference pool of 8 normal liver tissues.
2010-07-01 | E-GEOD-5093 | biostudies-arrayexpress
Project description:Rates of hepatocellular carcinoma (HCC) are increasing rapidly due to the epidemic of metabolic dysfunction-associated steatohepatitis (MASH). In addition to increased incidence, emerging evidence suggests that MASH driven HCC is associated with poor survival outcomes potentially due to the complex liver microenvironment which is characterized by hypoxia, steatosis, and fibrosis. Lenvatinib, is a multi-tyrosine kinase inhibitor, that is a standard of care therapy for unresected HCC, but 5-year survival rates are less than 20%. Therefore, developing treatments that inhibit cancer growth kinetics and target the tumor microenvironment to improve the therapeutic response in MASH-HCC are needed. Salsalate is a rheumatoid arthritis therapy that stimulates the AMP-activated protein kinase (AMPK) increasing fatty acid oxidation while reducing de-novo lipogenesis, fibrosis and cell proliferation pathways. Thus, we hypothesized that Salsalate could improve the therapeutic efficacy of Lenvatinib in MASH-HCC. In the current study, we show that treatment of human HCC cells with clinically relevant concentrations of Lenvatinib and Salsalate synergistically suppress proliferation and clonogenic survival, activate AMPK and inhibit the mTOR-HIF1a and Erk1/2 signaling pathways. In orthotopic xenograft and MASH-HCC mouse models Lenvatinib and Salsalate combination therapy suppressed angiogenesis and steatosis and fibrosis. RNA-sequencing revealed combination therapy enhanced mitochondria fatty acid oxidation and suppressed glycolysis, angiogenesis, fibrosis and cell cycle progression with regulatory network analysis suggesting a potential role for Activating transcription factor 3 (ATF3) and ETS-proto-oncogene-1 (ETS1). These data suggest that Lenvatinib and Salsalate combination therapy may have therapeutic potential for MASH-HCC due to effective metabolic rewiring and growth inhibition, leading to improvements in the liver microenvironment and inhibition of HCC proliferation.
2025-02-01 | GSE282660 | GEO
Project description:Immunosuppressive tumor microenvironments are common in cancers such as metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC). While immune cell metabolism influences effector function, the impact of tumor metabolism on immunogenicity is less understood. ATP citrate lyase (ACLY), a key enzyme linking catabolic and anabolic processes, supports lipid metabolism and gene regulation. Although ACLY inhibition shows anti-proliferative effects in various tumors, clinical translation has been limited by challenges in inhibitor development and compensatory metabolic pathways. Using a mouse model of MASH-driven HCC that mirrors human disease, genetic inhibition of ACLY in hepatocytes and tumors reduced neoplastic lesions by over 70%. To evaluate the therapeutic potential of this pathway, a novel small-molecule ACLY inhibitor, EVT0185 (6-[4-(5-carboxy-5-methyl-hexyl)-phenyl]-2,2-dimethylhexanoic acid), was identified via phenotypic screening. EVT0185 is converted to a CoA thioester in the liver by SLC27A2 with cryo-EM structural analysis revealing EVT0185-CoA directly interacts with ACLY’s CoA binding site. Oral delivery of EVT0185 in four mouse models of MASH-HCC dramatically reduces tumor burden as monotherapy and enhances efficacy of current standards of care including tyrosine kinase inhibitors and immunotherapies. Transcriptomic and spatial profiling in mice and humans linked reduced tumor ACLY with increases in CXCL13, tumor infiltrating B-cells and tertiary lymphoid structures. Remarkably, the depletion of B cells blocked the anti-tumor effects of ACLY depletion. Together, these findings illustrate how targeting tumor metabolism can rewire immune function and suppress cancer progression in MASH-HCC.
2025-09-17 | GSE296668 | GEO
Project description:Immunosuppressive tumor microenvironments are common in cancers such as metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC). While immune cell metabolism influences effector function, the impact of tumor metabolism on immunogenicity is less understood. ATP citrate lyase (ACLY), a key enzyme linking catabolic and anabolic processes, supports lipid metabolism and gene regulation. Although ACLY inhibition shows anti-proliferative effects in various tumors, clinical translation has been limited by challenges in inhibitor development and compensatory metabolic pathways. Using a mouse model of MASH-driven HCC that mirrors human disease, genetic inhibition of ACLY in hepatocytes and tumors reduced neoplastic lesions by over 70%. To evaluate the therapeutic potential of this pathway, a novel small-molecule ACLY inhibitor, EVT0185 (6-[4-(5-carboxy-5-methyl-hexyl)-phenyl]-2,2-dimethylhexanoic acid), was identified via phenotypic screening. EVT0185 is converted to a CoA thioester in the liver by SLC27A2 with cryo-EM structural analysis revealing EVT0185-CoA directly interacts with ACLY’s CoA binding site. Oral delivery of EVT0185 in four mouse models of MASH-HCC dramatically reduces tumor burden as monotherapy and enhances efficacy of current standards of care including tyrosine kinase inhibitors and immunotherapies. Transcriptomic and spatial profiling in mice and humans linked reduced tumor ACLY with increases in CXCL13, tumor infiltrating B-cells and tertiary lymphoid structures. Remarkably, the depletion of B cells blocked the anti-tumor effects of ACLY depletion. Together, these findings illustrate how targeting tumor metabolism can rewire immune function and suppress cancer progression in MASH-HCC.
2025-09-17 | GSE297190 | GEO
Project description:Introduction: The progression of hepatocellular carcinoma (HCC) is intricately linked to complex interactions within the tumor microenvironment (TME), where the reprogramming of tumor-associated macrophages (TAMs) plays a pivotal role. However, how HCC cells regulate TAM metabolism and function via extracellular vesicles, such as exosomes, remains incompletely understood. Methods: We isolated exosomes from HCC cell lines and co-cultured them with macrophages. Using proteomics, lipid analysis, flow cytometry, and animal models, we evaluated the effects of exosomal FABP5 on macrophage polarization and lipid metabolism. The role of FABP5 in tumor progression was assessed via in vivo experiments. Results: This study reveals that HCC cells release fatty acid-binding protein 5 (FABP5) via exosomes, transferring it to TAMs, thereby inducing significant lipid metabolism reprogramming in macrophages. Mechanistically, exosomal FABP5 promotes lipid accumulation by activating the PPARγ signaling pathway, while potentially inhibiting the PPARα signaling pathway to reduce fatty acid oxidation, ultimately driving TAM polarization towards an M2 phenotype, characterized by increased secretion of immunosuppressive cytokines and a pro-tumor phenotype. Clinical data analysis indicates that high FABP5 expression in HCC tissues correlates with poor patient prognosis. In liver-specific FABP5 knockout mouse models and HCC xenograft models, FABP5 deletion significantly suppressed tumor growth, reduced M2-type TAM infiltration and lipid accumulation, and enhanced anti-tumor immune responses. Conclusion: These findings collectively uncover exosomal FABP5 as a key mediator of metabolic and immune communication between HCC and TAMs, promoting HCC progression by remodeling the tumor immune microenvironment, and suggest FABP5 as a potential therapeutic target for HCC.
2025-09-12 | PXD068213 | Pride
Project description:We demonstrated that ACBP/DBI inhibition impaired hepatocarcinogenesis in NASH/MASH-driven HCC models. To further investigate its potential mechanisms at transcriptional level in NASH/MASH-driven HCC models, we performed Bulk RNA-seq analyses with liver tissues from the following three models, namely, (i) WD/CCl4 with tamoxifen inducible ACBP/DBI knout mice (Dbi-/- mice, Dbi+/+ mice as control) for in total 27 weeks; (ii) WD/CCl4 with KLH/KLH-ACBP immunized mice for in total 34 weeks; and (iii) HFD/DEN with KLH/KLH-ACBP immunized miceI for a total of 36 weeks.
2025-04-18 | GSE255799 | GEO
Project description:Immunosuppressive tumor microenvironments are common in cancers such as metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma. To further investigate tumor–immune interactions, we performed spatial transcriptomics on livers from MASH-driven HCC mouse models (WD-DEN, WT or Acly KO mice and from WD-CCL4, Vehicle, or EVT0185 (100mg/kg) treated mice). GO enrichment analysis of spatially resolved tumor cells showed increased fatty acid and lipid metabolism in both Acly KO and EVT0185-treated mice Spatial analysis also revealed a selective increase in B cells, but not T cells, macrophages, or NKT cells, in tumors from Acly KO and EVT0185-treated mice.
2025-06-30 | GSE297081 | GEO
Project description:Limb expression 1-like protein (LIX1L) plays important role in various liver disorders, but its role and underlying mechanism in nonalcoholic hepatitis (NASH) and HCC progression remains obscure. Here, we report that LIX1L functions as a key integrative regulator linking lipid metabolism and inflammation, adipose tissue dysfunction and hepatic microenvironment reprogramming which promotes NASH progression. LIX1L significantly upregulated in NAFLD/NASH patients, mouse models and palmitic acid-stimulated hepatocytes. Lix1l deletion inhibits lipid deposition, inflammatory response and fibrosis in liver as well as adipocyte differentiation by downregulation of fatty acid translocase CD36 expression, alleviating NASH and associated HCC progression. In contrast, adeno-associated virus (AAV)-mediated LIX1L overexpression exacerbates NASH progression in mice. Mechanistically, metabolic stress promotes PARP1 mediated poly-ADP-ribosylation (PARylation) of LIX1L, subsequently increasing the stability and RNA binding ability of LIX1L protein. LIX1L binds to AU-rich element (ARE) in the 3’ untranslated region (UTR) of CD36 mRNA, thus attenuating CD36 mRNA decay. In NASH and associated HCC mouse models, LIX1L deficiency-mediated downregulation of CD36 suppresses adipogenesis, hepatic lipid uptake, and reprograms the tumor-prone liver microenvironment with increased cytotoxic T lymphocytes (CTLs), reduced immunosuppressive cell proportions. These data indicate a systematic function of LIX1L in the pathogenesis of NASH and underscore the PARP1/LIX1L/CD36 axis as a potential target for treatment of NASH and associated HCC.
2024-04-25 | GSE264479 | GEO
Project description:To determine the role of the hepatic microenvironment in HCC metastasis, we compared the gene expression profiles of 20 noncancerous surrounding hepatic tissues from two HCC patient groups, those with primary HCC together with venous metastasis which we termed a metastasis-inclined microenvironment (MIM) and those with HCC without detectable metastasis, which we termed a metastasis-averse microenvironment (MAM). Keywords: disease state design
2006-08-17 | GSE5093 | GEO