A genetic-metabolic axis for metastatic liver organotropism
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA778715 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16852800.fastq.gz | Fastqsanger.gz | |||
| SRR16852900.fastq.gz | Fastqsanger.gz | |||
| SRR16853001_1.fastq.gz | Fastqsanger.gz | |||
| SRR16853001_2.fastq.gz | Fastqsanger.gz | |||
| SRR16852802.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 152 |
Similar Datasets
Project description:To generate CRISPR/Cas9 knockout screen, we used mouse Kinome CRISPR Knockout Library (Brie) (Addgene # 75316) purchased from addgene. The mouse kinase sgRNA pool includes 2,852 sgRNAs targeting 713 kinase genes and 100 control non-targeting sgRNAs. Cas9 expressing HCmel12 melanoma cells were edited for 14 days, and tumor cells were injected for metastasis screening studies. RNA-seq data: HCmel12 melanoma cells and CRISPR knockout HCmel12 melanoma cells - Pip4k2c KO were treated for 4 hours with insulin. Then cells were lysed in RLT buffer and used to perform mRNA profiling. We performed single-cell RNA-sequencing (scRNA-seq) of eight mice with concurrent liver and lung metastasis. A total of 95,606 cells expressing 19,624 genes were included for downstream analyses. Bulk RNA-sequencing analysis of 15 human melanoma liver metastasis samples from FFPE sample. Tumor areas were macro-dissected and RNA was extracted using Qiagen kit All Prep DNA/RNA FFPE Kit (Catalog Number 80234), concentration was quantified using Qu-bit and stored at-80 °C until use.
2023-08-29 | GSE188391 | GEO
Project description:Inflammatory signaling in the liver reshapes numerous transcriptional programs, but the mechanisms by which innate immune pathways actively repress metabolic gene expression remain poorly understood. Here we show that IRF3, a master regulator of innate immunity that is activated during alcohol-associated liver disease, suppresses the hepatokine FGF21 and broader metabolic gene programs through a non-canonical transcriptional mechanism. IRF3 does not directly occupy metabolic gene loci but instead transcriptionally induces POLR2G, a core RNA polymerase II subunit, through promoter-proximal interferon-stimulated response elements. Elevated POLR2G selectively accumulates at metabolic gene promoters, reduces RNA polymerase II recruitment, and represses transcription of fatty acid oxidation and lipid metabolism genes. This regulatory axis operates in vivo, is conserved from yeast to mammals, and is evident in human alcohol-associated liver disease. These findings identify an IRF3-POLR2G axis that repurposes core transcriptional machinery to coordinate a metabolic-to-inflammatory transcriptional switch in the liver.
2026-05-15 | GSE331028 | GEO
Project description:Inflammatory signaling in the liver reshapes numerous transcriptional programs, but the mechanisms by which innate immune pathways actively repress metabolic gene expression remain poorly understood. Here we show that IRF3, a master regulator of innate immunity that is activated during alcohol-associated liver disease, suppresses the hepatokine FGF21 and broader metabolic gene programs through a non-canonical transcriptional mechanism. IRF3 does not directly occupy metabolic gene loci but instead transcriptionally induces POLR2G, a core RNA polymerase II subunit, through promoter-proximal interferon-stimulated response elements. Elevated POLR2G selectively accumulates at metabolic gene promoters, reduces RNA polymerase II recruitment, and represses transcription of fatty acid oxidation and lipid metabolism genes. This regulatory axis operates in vivo, is conserved from yeast to mammals, and is evident in human alcohol-associated liver disease. These findings identify an IRF3-POLR2G axis that repurposes core transcriptional machinery to coordinate a metabolic-to-inflammatory transcriptional switch in the liver.
2026-05-15 | GSE331025 | GEO
Project description:Inflammatory signaling in the liver reshapes numerous transcriptional programs, but the mechanisms by which innate immune pathways actively repress metabolic gene expression remain poorly understood. Here we show that IRF3, a master regulator of innate immunity that is activated during alcohol-associated liver disease, suppresses the hepatokine FGF21 and broader metabolic gene programs through a non-canonical transcriptional mechanism. IRF3 does not directly occupy metabolic gene loci but instead transcriptionally induces POLR2G, a core RNA polymerase II subunit, through promoter-proximal interferon-stimulated response elements. Elevated POLR2G selectively accumulates at metabolic gene promoters, reduces RNA polymerase II recruitment, and represses transcription of fatty acid oxidation and lipid metabolism genes. This regulatory axis operates in vivo, is conserved from yeast to mammals, and is evident in human alcohol-associated liver disease. These findings identify an IRF3-POLR2G axis that repurposes core transcriptional machinery to coordinate a metabolic-to-inflammatory transcriptional switch in the liver.
2026-05-15 | GSE331029 | GEO
Project description:Inflammatory signaling in the liver reshapes numerous transcriptional programs, but the mechanisms by which innate immune pathways actively repress metabolic gene expression remain poorly understood. Here we show that IRF3, a master regulator of innate immunity that is activated during alcohol-associated liver disease, suppresses the hepatokine FGF21 and broader metabolic gene programs through a non-canonical transcriptional mechanism. IRF3 does not directly occupy metabolic gene loci but instead transcriptionally induces POLR2G, a core RNA polymerase II subunit, through promoter-proximal interferon-stimulated response elements. Elevated POLR2G selectively accumulates at metabolic gene promoters, reduces RNA polymerase II recruitment, and represses transcription of fatty acid oxidation and lipid metabolism genes. This regulatory axis operates in vivo, is conserved from yeast to mammals, and is evident in human alcohol-associated liver disease. These findings identify an IRF3-POLR2G axis that repurposes core transcriptional machinery to coordinate a metabolic-to-inflammatory transcriptional switch in the liver.
2026-05-15 | GSE331024 | GEO
Project description:Through an integrated transcriptome analysis of orthotopic colorectal cancer tumor-bearing mice and sham-operation mice, we showed the distinct immune microenvironment of pre-metastatic liver and identified MDSCs as the dominated cell type mediating pre-metastatic niche formation. MDSCs instead of other immune cell types were highly infiltrated in the pre-metastatic liver when compared with normal liver. Notably, immunosuppressive factors released by MDSCs such as HIF1α, iNOS, TGFβ were significantly up-regulated in the pre-metastatic liver. Increasing immune checkpoint molecules expression also reflected an immunosuppressive condition of pre-metastatic liver. The primary tumor may induce MDSCs accumulation via metabolic mechanism including glycolysis/gluconeogenesis, HIF-1 signaling pathway, and CCL28 chemokine axis. This study depicts the immune cell landscape of pre-metastatic cancer and primary CRC tumor, and provides insights into how MDSCs reshape the pre-metastatic niche facilitating circulating cancer cells colonization.
2020-04-30 | GSE147044 | GEO
Project description:Inflammatory signaling in the liver reshapes numerous transcriptional programs, but the mechanisms by which innate immune pathways actively repress metabolic gene expression remain poorly understood. Here we show that IRF3, a master regulator of innate immunity that is activated during alcohol-associated liver disease, suppresses the hepatokine FGF21 and broader metabolic gene programs through a non-canonical transcriptional mechanism. IRF3 does not directly occupy metabolic gene loci but instead transcriptionally induces POLR2G, a core RNA polymerase II subunit, through promoter-proximal interferon-stimulated response elements. Elevated POLR2G selectively accumulates at metabolic gene promoters, reduces RNA polymerase II recruitment, and represses transcription of fatty acid oxidation and lipid metabolism genes. This regulatory axis operates in vivo, is conserved from yeast to mammals, and is evident in human alcohol-associated liver disease. These findings identify an IRF3-POLR2G axis that repurposes core transcriptional machinery to coordinate a metabolic-to-inflammatory transcriptional switch in the liver.
2026-05-15 | GSE331026 | GEO
Project description:Inflammatory signaling in the liver reshapes numerous transcriptional programs, but the mechanisms by which innate immune pathways actively repress metabolic gene expression remain poorly understood. Here we show that IRF3, a master regulator of innate immunity that is activated during alcohol-associated liver disease, suppresses the hepatokine FGF21 and broader metabolic gene programs through a non-canonical transcriptional mechanism. IRF3 does not directly occupy metabolic gene loci but instead transcriptionally induces POLR2G, a core RNA polymerase II subunit, through promoter-proximal interferon-stimulated response elements. Elevated POLR2G selectively accumulates at metabolic gene promoters, reduces RNA polymerase II recruitment, and represses transcription of fatty acid oxidation and lipid metabolism genes. This regulatory axis operates in vivo, is conserved from yeast to mammals, and is evident in human alcohol-associated liver disease. These findings identify an IRF3-POLR2G axis that repurposes core transcriptional machinery to coordinate a metabolic-to-inflammatory transcriptional switch in the liver.
2026-05-15 | GSE331023 | GEO
Project description:Metabolic rewiring is essential for breast tumor growth and progression to metastatic disease, yet little is known regarding how cancer cells modify their acquired metabolic programs in response to different metastatic microenvironments. Transcriptional and metabolomic analysis have previously shown that liver-metastatic breast cancer cells adopt an intrinsic metabolic profile characterized by increased HIF-1α activity and dependence on glycolysis. Stable isotope tracing analysis (SITA) performed in vivo confirmed that the glycolytic nature of liver-metastatic breast cancer cells is retained when these cells are grown as primary tumors or as liver metastases. However, our data also reveal that unique metabolic adaptations are specifically induced by the liver microenvironment. Indeed, liver metastases display elevated expression of genes involved in glutathione (GSH) biosynthesis and reactive oxygen species (ROS) detoxification when compared to primary tumors. Moreover, breast cancer liver metastases rely strongly on glucose and glutamine-derived carbons to support de novo GSH synthesis. Glutathione is a tripeptide that acts as a major scavenger for reactive oxygen species (ROS). Liver metastases display reduced levels of 8-Oxo-2'-deoxyguanosine, confirming their increased capacity to buffer ROS. We demonstrated the dependence of liver metastases formation on these distinct metabolic adaptations by depleting glutamate-cysteine ligase (Gcl), the rate-limiting enzyme in glutathione biosynthesis. Gcl depletion, and decreased GSH levels, strongly reduced the capacity of liver-metastatic cells to form distant metastasis within the liver. We performed gene expression analysis of liver metastasis and primary tumors from liver-metastatic breast cancer cells derived from 4T1 cells. 4T1-2776 (76) and 4T1-2792 (92) cells were injected in the mammary fat pads of BALB/c and grown as primary tumors or were grown as liver metastasis after splenic injection. Tissues were harvested from primary tumors and liver metastasis and submitted to laser-capture microdissection (LCM). For liver metastasis, tumour tissue was harvested at 10 days, 2 weeks and 3 weeks after splenic injection. For each time point, tissue was isolated from the tumor centre (core), a peripheral area of the tumor (margin), a region of the liver proximal to the tumor (adjacent) and a region of the liver far from the tumor (distant). For primary tumors from 4T1-2776 cells (1034, 1036, 1043) and 4T1-2792 (MFP2L, MFP3L, MFP5L) tissue was collected from the tumor core and margin, at the experimental endpoint.
2023-07-25 | GSE238214 | GEO
Project description:Estrogen receptor-positive (ER+) metastatic tumors contribute to nearly 70% of breast cancer-related deaths. Most patients with ER+ metastatic breast cancer (MBC) undergo treatment with the estrogen receptor agonist fulvestrant (Fulv) as standard of care. Yet, among such patients, metastasis in liver is associated with reduced overall survival compared to other metastasis sites. The factors underlying the reduced responsiveness of liver metastases to ER agonists remain unknown, impeding the development of more effective treatment approaches to improve outcomes for patients with ER+ liver metastases. We therefore evaluated site-specific changes in MBC cells and determined the mechanisms through which the liver metastatic niche specifically influences ER+ tumor metabolism and drug resistance. We characterized ER activity of MBC cells both in vitro, using a novel system of tissue-specific extracellular matrix hydrogels representing the stroma of ER+ tumor metastatic sites (liver, bone), and in vivo, in liver and lung metastasis mouse models. ER+ metastatic liver tumors and MBC cells grown in liver hydrogels displayed upregulated expression of glucose metabolism enzymes in response to Fulv. Furthermore, differential ERαERα activity, but not expression, was detected in liver hydrogels. In vivo, increased glucose metabolism led to increased glycogen deposition in liver metastatic tumors, while a fasting-mimicking diet increased efficacy of Fulv treatment to reduce the metastatic burden. Our findings identify a novel mechanism of endocrine resistance driven by the liver tumor microenvironment. These results may guide the development of dietary strategies to circumvent drug resistance in liver metastasis, with potential applicability in other metastatic diseases.
2022-06-15 | GSE184156 | GEO