Inhibition of ACLY enhances tumor immunogenicity and resolves MASH-driven HCC
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1262480 | ENA |
REPOSITORIES: ENA
Similar Datasets
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: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: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:De novo lipogenesis is activated in most cancers. Several lipogenic enzymes are implicated in oncogenesis and represent potential cancer therapeutic targets. RNA interference-mediated depletion of ATP citrate lyase (ACLY), the enzyme that catalyzes the first step of de novo lipogenesis, leads to growth suppression in a subset of human cancer cells. Here we demonstrate the molecular basis and potential biomarkers for ACLY-targeting therapy. First, suppression of cancer cell growth by ACLY depletion involves down-regulation of fatty acid elongase ELOVL6 at the transcriptional level. Lipid profiling revealed that ACLY depletion alters fatty acid composition in triglyceride; increased palmitate and decreased longer fatty acids, in accordance with ELOVL6 down-regulation. Second, ACLY depletion increases reactive oxygen species (ROS), whereas addition of antioxidant reduces ROS and attenuates the growth suppression. Third, ACLY depletion or ROS stimulation induce phosphorylation of AMP-activated protein kinase (AMPK), a sensor of energy and lipid metabolism. Analysis of various cancer cell lines revealed that the levels of AMPK phosphorylation (p-AMPK) correlate with the basal ROS levels, and that cancer cells with low basal p-AMPK (i.e., low basal ROS) levels are highly susceptible to ACLY depletion-mediated growth suppression. Finally, in clinical colon cancer tissues, p-AMPK levels are significantly decreased in aggressive tumors and correlate with the levels of 8-hydroxydeoxyguanosine, a hallmark of ROS stimulation. Together, these data suggest that ACLY inhibition suppresses cancer growth via palmitate-mediated lipotoxicity, and p-AMPK could be a predictive biomarker for its therapeutic outcome. Two cell lines are treated with ACLY siRNA. The samples include controls of each cell line.
2014-04-13 | E-GEOD-37243 | 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:We identified ACBP/DBI as a critical regulator in the pathogenesis of hepatocellular carcinoma (HCC), with its inhibition significantly impairing hepatocarcinogenesis in MASH-driven HCC models. To further elucidate the underlying transcriptional mechanisms, we performed spatial transcriptomic analyses using formalin-fixed, paraffin-embedded (FFPE) liver tissues from the following two experimental models: (i) Western diet (WD) and CCl₄-treated mice with tamoxifen-inducible ACBP/DBI knockout (Dbi⁻/⁻ mice), with Dbi⁺/⁺ littermates serving as controls, after a total of 27 weeks; (ii) WD and CCl₄-treated mice immunized with either keyhole limpet hemocyanin (KLH) alone or KLH-ACBP conjugate, after a total of 34 weeks.
2025-07-18 | GSE296545 | GEO
Project description:Background:
HCC incidence is increasing worldwide due to the obesity epidemic, which drives metabolic dysfunction-associated steatohepatitis (MASH) that can lead to HCC. However, the molecular pathways driving MASH-HCC are poorly understood. We have previously reported that male mice with haploinsufficiency of hypoxia-associated factor, HAF (SART1+/-) spontaneously develop MASH-HCC. However, the cell type(s) responsible for HCC associated with HAF loss are unclear.
Results:
We generated SART1-floxed mice, which were crossed with mice expressing Cre-recombinase within hepatocytes (Alb-Cre; hepS-/-) or myeloid cells (LysM-Cre, macS-/-). HepS-/- mice (both male and female) developed HCC associated with profound inflammatory and lipid dysregulation suggesting that HAF protects against HCC primarily within hepatocytes. HAF-deficient hepatocytes showed decreased P-p65 and P-p50 and in many components of the NF-kB pathway, which was recapitulated using HAF siRNA in vitro. HAF depletion also triggered apoptosis, suggesting that HAF protects against HCC by suppressing hepatocyte apoptosis. We show that HAF regulates NF-kB activity by regulating transcription of TRADD and RIPK1. Mice fed a high-fat diet (HFD) showed marked suppression of HAF, P-p65 and TRADD within their livers after 26 weeks, but showed profound upregulation of these proteins after 40 weeks, implicating deregulation of the HAF-NF-kB axis in the progression to MASH. In humans, HAF was significantly decreased in livers with simple steatosis but significantly increased in HCC compared with normal liver.
Conclusions:
HAF is novel transcriptional regulator of the NF-kB pathway and is a key determinant of cell fate during progression to MASH and MASH-HCC.
| MSV000095959 | MassIVE
Project description:Tumor-associated neutrophils (TANs) are heterogeneous; thus, their roles in tumor development could vary depending on the cancer type. Here, we showed that TANs were more detrimental to metabolic dysfunction-associated steatohepatitis hepatocellular carcinoma (MASH-related HCC) than to viral-associated HCC. We attributed this difference to the predominance of SiglecFhi TANs in MASH-related HCC tumors. Linoleic acid and GM-CSF, which are commonly elevated in the MASH-related HCC microenvironment, fostered the development of this c-Myc-driven TAN subset. Through TGFβ secretion, SiglecFhi TANs promoted HCC stemness, proliferation, and migration. Importantly, SiglecFhi TANs supported immune evasion by directly suppressing the antigen presentation machinery of tumor cells. SiglecFhi TAN removal increased the immunogenicity of a MASH-related HCC model and sensitized it to immunotherapy. Likewise, a high SiglecFhi TAN signature was associated with poor prognosis and immunotherapy resistance in HCC patients. Overall, our study highlights the importance of understanding TAN heterogeneity in cancer to improve therapeutic development
2024-11-19 | GSE240839 | GEO
Project description:Tumor-associated neutrophils (TANs) are heterogeneous; thus, their roles in tumor development could vary depending on the cancer type. Here, we showed that TANs were more detrimental to metabolic dysfunction-associated steatohepatitis hepatocellular carcinoma (MASH-related HCC) than to viral-associated HCC. We attributed this difference to the predominance of SiglecFhi TANs in MASH-related HCC tumors. Linoleic acid and GM-CSF, which are commonly elevated in the MASH-related HCC microenvironment, fostered the development of this c-Myc-driven TAN subset. Through TGFβ secretion, SiglecFhi TANs promoted HCC stemness, proliferation, and migration. Importantly, SiglecFhi TANs supported immune evasion by directly suppressing the antigen presentation machinery of tumor cells. SiglecFhi TAN removal increased the immunogenicity of a MASH-related HCC model and sensitized it to immunotherapy. Likewise, a high SiglecFhi TAN signature was associated with poor prognosis and immunotherapy resistance in HCC patients. Overall, our study highlights the importance of understanding TAN heterogeneity in cancer to improve therapeutic development
2024-11-19 | GSE240838 | GEO
Project description:In order to propagate a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME) stresses, such as hypoxia or lactic acidosis. To systematically identify genes that modulate cancer cell survival under stresses, we performed genome-wide shRNA screens under hypoxia or lactic acidosis. We discovered that genetic depletion of acetyl-CoA carboxylase (ACACA or ACC1) or ATP citrate lyase (ACLY) protected cancer cells from hypoxia-induced apoptosis. Additionally, loss of ACLY or ACC1 reduced levels and activities of the oncogenic transcription factor ETV4. Silencing ETV4 also protected cells from hypoxia-induced apoptosis and led to remarkably similar transcriptional responses as with silenced ACLY or ACC1, including an anti-apoptotic program. Metabolomic analysis found that while α-ketoglutarate levels decrease under hypoxia in control cells, α-ketoglutarate is paradoxically increased by hypoxia when ACC1 or ACLY are depleted. Supplementation with α-ketoglutarate rescued the hypoxia-induced apoptosis and recapitulated the decreased expression and activity of ETV4 via an epigenetic mechanism. Therefore, ACC1 and ACLY regulate the levels of ETV4 under hypoxia via increased α-ketoglutarate. These results reveal that ACC1/ACLY- α-ketoglutarate-ETV4 is a novel means by which metabolic states regulate transcriptional output for life vs. death decisions under hypoxia. Since many lipogenic inhibitors are under investigation as cancer therapeutics, our findings suggest that the use of these inhibitors will need to be carefully considered with respect to oncogenic drivers, tumor hypoxia, progression and dormancy. More broadly, our screen provides a framework for studying additional tumor cell stress-adaption mechanisms in the future. DESIGN: H1975 lung cancer cells transduced with a scramble shRNA hairpin or two different shRNAs against ACLY, ACC1, or ETV4 under hypoxia.
2015-12-10 | E-GEOD-61286 | biostudies-arrayexpress