Transcriptional profiling of liver, neutrophils and T cells from a mouse model of NASH-HCC
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ABSTRACT:
PROVIDER: PRJNA945918 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23900800_1.fastq.gz | Fastqsanger.gz | |||
| SRR23900800_2.fastq.gz | Fastqsanger.gz | |||
| SRR23900900_1.fastq.gz | Fastqsanger.gz | |||
| SRR23900900_2.fastq.gz | Fastqsanger.gz | |||
| SRR23900801_1.fastq.gz | Fastqsanger.gz |
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Project description:Transcriptional profiling by bulk RNA sequencing of murine livers or sorted immune cells, from DEN ALIOS NASH-HCC mouse model. Mice treated with CXCR2i (AZD5069) monotherapy, anti-PD1 monotherapy, or combination CXCR2i, anti-PD1 treatment. Published in doi: 10.1136/gutjnl-2021-326259
2023-03-22 | GSE227620 | GEO
Project description:Hepatocellular carcinoma (HCC), which accounts for 90% of all primary livers tumors, is the fourth most common cancer in the world. The development of HCC is a long-term and complex process, and uncovering the molecular mechanisms associated with HCC development is critical for the disease diagnosis, prevention, and treatment. Exploring these mechanisms using human HCC samples is desirable, but frequently impractical, with a number of limitations and shortcomings. The STAMTM (Stelic Institute & Co, Tokyo, Japan) mouse model of NASH-associated liver carcinogenesis is considered a useful and relevant model for investigating the molecular pathogenesis of NASH-derived HCC. This model resembles the human HCC development associated with progression from simple steatosis to NASH, fibrosis, and HCC. In the present study, by using high-throughput whole genome microarrays (SurePrint G3 Mouse Gene Expression v2, 8x60K; Agilent Technologies, Santa Clara, CA), we examined the transcriptomic profiles in the livers of STAMTM mice at different stages of liver carcinogenesis, including steatosis (6 week time interval), NASH (8 weeks), fibrotic stage (12 weeks), and in full-fledged HCC (20 weeks). The results of microarray analyses showed significant progressive changes in hepatic gene expression during the development of HCC. A total of 970, 1462, 2742, and 2857 of differentially expressed genes were identified in the livers at 6, 8, 12, and 20 weeks, respectively. Detailed analysis of these differentially expressed genes will benefit the understanding of the underlying mechanisms of non-alcoholic fatty liver disease-derived HCC. Transcriptomic profile in the liver of STAM mice at 6 weeks (steatosis; n=3), 8 weeks (steatohepatitis; n=3) 12 weeks (fibrosis; n=4) and 20 weeks (HCC-stage tumor tissue, n=4) weeks. Age-matched control samples were also analyzed.
2016-06-22 | E-GEOD-83596 | biostudies-arrayexpress
Project description:Non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is a significant risk factor for hepatocellular carcinoma (HCC). However, a preclinical model of progressive NAFLD/NASH is largely lacking. Here, we report that mice with hepatocyte-specific deletion of Tid1, encoding a mitochondrial cochaperone, tended to develop NASH-dependent HCC. Mice with hepatic Tid1 deficiency showed impairing mitochondrial function and causing fatty acid metabolic dysregulation; meanwhile, sequentially developed fatty liver, NASH, and cirrhosis/HCC in a diethylnitrosamine (DEN) induced oxidative environment. The pathological signatures of human NASH, including cholesterol accumulation and activation of inflammatory and apoptotic signaling pathways, are also present in these mice. Clinically, low Tid1 expression was associated with unfavorable prognosis in patients with HCC. Empirically, hepatic Tid1 deficiency directly disrupts entire mitochondria that play a key role in the NASH-dependent HCC development. Overall, we established a new mouse model that develops NASH-dependent HCC and provides a promising approach to improve the treatment.
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Project description:We applied RNA sequencing (RNA-seq) to study the gene expression profile in the liver of GAN DIO-NASH-HCC mice (non-tumorous tissue samples, n=9; tumor samples, n=9) and chow-fed controls (healthy liver samples, n=5)). Comparing tumour tissue of GAN DIO-NASH-HCC mice to healthy chow-fed controls, we find that tumors of GAN DIO-NASH-HCC mice show widespread regulations of genes associated with human HCC. Human HCC can be classified into three categories (S1-S3). Using the human S1-S3 gene classification described by Hoshida Y. et al. (2009), we find that GAN DIO-NASH-HCC tumors resemble the human S1 class of proliferating HCC tumors with poor prognosis.
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Project description:Hepatocellular carcinoma (HCC) has dismal treatment responses to systemic therapies and is caused by both, viral and non-viral etiologies, including non-alcoholic steatohepatitis (NASH) 1–5. NASH - triggered by high caloric intake and sedentary lifestyle - has become an important driver for HCC development. Immunotherapy has been recently approved for HCC but stratification of responders versus non-responders has remained an unmet need 5–8. Here, we found a progressive accumulation of non-classical activated CD8+PD-1+ T-cells in livers of NASH-affected patients and mice. PD-L1/PD-1-targeted immunotherapy of NASH-induced HCC administered either at cancer-initiation or after cancer-establishment lacked beneficial effects in mice. On the contrary, PD-1-targeted immunotherapy drove hepatic necro-inflammation and increased liver cancer incidence, tumor number, and nodule size. Anti-CD8 or anti-CD8/anti-NK1.1 treatment suppressed liver cancer development, implicating CD8+ T-cells as liver cancer drivers in the context of NASH. In line, PD-1-/- mice challenged with a NASH-inducing diet displayed early-onset of liver cancer. Mechanistically, PD-1-targeted immunotherapy triggered necro-inflammation and a pro-tumorigenic environment in the context of NASH, increasing the abundance of hepatic TOX+CXCR6+ expressing CD8+PD-1+ TNF+ T-cells. Anti-CD8/anti-PD-1 or anti-TNF/anti-PD-1, but not anti-CD4/anti-PD-1 treatment reverted anti-PD1 treatment-related increase of liver inflammation, NASH severity and tumorigenesis. Gene expression profile and increased abundance of murine hepatic CD8+PD-1+ T-cells were corroborated in human CD8+PD-1+ T cells derived from NASH patients. In a meta-analysis of clinical trials testing PD-1-targeting immune checkpoint inhibitors alone (i.e. pembrolizumab) or in combination in 1656 patients with advanced HCC, immunotherapy was not favorable over to control treatment in non-viral- when compared to viral-related HCC. Similarly, in two clinical cohorts tested, patients with NASH-driven HCC had a significantly worse overall survival with PD-1-targeted immunotherapy than HCC patients with other etiologies. Our data identify non-viral etiologies, particularly NASH, as potentially non-responsive in the context of HCC immunotherapy, providing a strong rational basis for patient stratification.
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Project description:Single-nucleus RNA-seq of NASH HCC liver tissue
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Project description:Paraffin-embedded paired tumor and peri-carcinoma tissues (n=4) were obtained from the Biorepository of Fudan University Institute of Liver Cancer, which were used for the Affymetrix microarray analysis To investigate the progression of NASH to HCC, we established a differential gene expression profile by analyzing significant expression changes in pathologically confirmed NASH-HCC and peri-carcinoma specimens using Affymetrix microarrays.
2020-06-01 | GSE99807 | GEO
Project description:RNAseq analysis that will help to define 1) the circadian dysfunction induced liver transcriptome that drives fatty liver disease induced hepatocarcinogenesis in a humanized mouse model; 2) the currently unknown circadian profile of NASH and HCC gene signatures specifically associated with human hepatocytes and liver or tumor microenvironment. These gene signatures will significantly advance our understanding of the mechanism of spontaneous HCC and have important preclinic values for developing novel therapeutic strategies for prevention and treatment of HCC in humans.
2025-01-01 | GSE205881 | GEO
Project description:The mammalian liver comprises heterogeneous cell types within its tissue microenvironment that respond to physiological cues and undergo pathophysiological reprogramming in disease states, such as nonalcoholic steatohepatitis (NASH). Patients with NASH are at increased risk for the development of hepatocellular carcinoma (HCC). However, the molecular and cellular nature of liver microenvironment remodeling that links NASH to liver carcinogenesis remains obscure. Here we show that diet-induced NASH is characterized by induction of tumor-associated macrophage (TAM)-like macrophages and exhaustion of cytotoxic T cells in mouse liver. The adipose-derived endocrine factor Neuregulin 4 (NRG4) serves as a hormonal checkpoint that restrains this pathological reprogramming during NASH. NRG4 deficiency exacerbates the induction of tumor-prone liver immune microenvironment and NASH-associated HCC, whereas transgenic NRG4 overexpression elicits protective effects in mice. In a therapeutic setting, recombinant NRG4 protein exhibits remarkable efficacy in inhibiting HCC in mice with NASH, thereby paving the way for future therapeutic development.
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