Pharmacological inhibition of LIFR impairs ovarian cancer progression by blocking LIF/LIFR autocrine loop
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA992123 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25179881.fastq.gz | Fastqsanger.gz | |||
| SRR25179882.fastq.gz | Fastqsanger.gz | |||
| SRR25179883.fastq.gz | Fastqsanger.gz | |||
| SRR25179884.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 4 of 4 |
Similar Datasets
Project description:We examined the transcriptional chagnes modulated by LIFR inhibitory compound EC359 by perfroming global transcriptome analysis. ES2 cells were treated with vehicle or EC359 for 12 h and the RNA was isolated and utilized for RNA-seq analysis. Our results demonstrated that EC359 modulated unique pathways including oxidative phosphorylation, Glutathione signaling, JNK signaling, NRF2 signaling, ovarian cancer signaling, hypoxia signaling and apoptotic pathways.
2024-05-29 | GSE236743 | GEO
Project description:Super-enhancers (SEs) have been recognized as key epigenetic regulators underlying cancer stemness and malignant traits by aberrant transcriptional control and promising therapeutic targets against human cancers. However, the SE landscape and their roles during head and neck squamous cell carcinoma (HNSCC) development especially in cancer stem cells (CSCs) maintenance remain underexplored yet. Here, we identified leukemia inhibitory factor (LIF)-SE as a representative oncogenic SE to activate LIF transcription in HNSCC. LIF secreted from cancer cells and cancer-associated fibroblasts promotes cancer stemness by driving SOX2 transcription in an autocrine or paracrine manner, respectively. Mechanistically, enhancer elements E1, 2, 4 within LIF-SE recruited SOX2/SMAD3/BRD4/EP300 to facilitate LIF transcription; LIF activated downstream LIFR-STAT3 signaling to drive SOX2 transcription, thus forming a previously unknown regulatory feedback loop (LIF-SE-LIF/LIFR-STAT3-SOX2) to maintain LIF overexpression and CSCs stemness. Clinically, increased LIF abundance in clinical samples correlated with malignant clinicopathological features and patient prognosis; higher LIF concentrations in presurgical plasma were negatively associated with patient survival and dramatically diminished following cancer eradication. Therapeutically, pharmacological targeting LIF-SE-LIF/LIFR-STAT3 significantly impaired tumor growth and reduced CSC subpopulations in HNSCC xenograft and PDX models. Our findings reveal a hitherto uncharacterized LIF-SE-mediated auto-regulatory loop in regulating HNSCC stemness and highlight LIF as a novel non-invasive biomarker and potential therapeutic target for HNSCC.
2024-11-06 | GSE274995 | GEO
Project description:Super-enhancers (SEs) have been recognized as key epigenetic regulators underlying cancer stemness and malignant traits by aberrant transcriptional control and promising therapeutic targets against human cancers. However, the SE landscape and their roles during head and neck squamous cell carcinoma (HNSCC) development especially in cancer stem cells (CSCs) maintenance remain underexplored yet. Here, we identified leukemia inhibitory factor (LIF)-SE as a representative oncogenic SE to activate LIF transcription in HNSCC. LIF secreted from cancer cells and cancer-associated fibroblasts promotes cancer stemness by driving SOX2 transcription in an autocrine or paracrine manner, respectively. Mechanistically, enhancer elements E1, 2, 4 within LIF-SE recruited SOX2/SMAD3/BRD4/EP300 to facilitate LIF transcription; LIF activated downstream LIFR-STAT3 signaling to drive SOX2 transcription, thus forming a previously unknown regulatory feedback loop (LIF-SE-LIF/LIFR-STAT3-SOX2) to maintain LIF overexpression and CSCs stemness. Clinically, increased LIF abundance in clinical samples correlated with malignant clinicopathological features and patient prognosis; higher LIF concentrations in presurgical plasma were negatively associated with patient survival and dramatically diminished following cancer eradication. Therapeutically, pharmacological targeting LIF-SE-LIF/LIFR-STAT3 significantly impaired tumor growth and reduced CSC subpopulations in HNSCC xenograft and PDX models. Our findings reveal a hitherto uncharacterized LIF-SE-mediated auto-regulatory loop in regulating HNSCC stemness and highlight LIF as a novel non-invasive biomarker and potential therapeutic target for HNSCC.
2024-11-06 | GSE274994 | GEO
Project description:Oncostatin M (OSM) and Leukemia Inhibitory Factor (LIF) signal within cells via the gp130 (Il6st) coreceptor bound either to the LIF receptor (LIFR) or the oncostatin M receptor (OSMR), but whether murine OSM can act through both receptors is controversial. Both LIF and OSM stimulate bone formation, inhibit adipocyte differentiation, and promote osteoclast differentiation, but our earlier work suggested this may depend on the receptor subtype used. This project aimed to identify those gene targets regulated by murine OSM via OSMR and LIFR by using wild type and OSMR null primary osteoblasts. Cells were differentiated to their most mature state (i.e. osteocytes) because the only prior target gene known to be regulated by murine OSM via the LIFR was an osteocyte-specific gene, sclerostin.
2016-08-17 | GSE83418 | GEO
Project description:Dlx3 over-expression in mouse embryonic fibroblasts changed the expression level of numerous genes involved in osteogenesis and embryonic stem cell-related pathways as revealed by microarray analysis. From the list of Dlx3 modulated genes we focused our attention on the study of two candidates, Lifr and Chrdl1. Chromatin immunoprecipitation demonstrated the recruitment of Dlx3 transcription factor to the promoters of Lifr and Chrdl1, and luciferase assays confirmed the role of Dlx3 in the regulation of Lifr expression. Over-expression of Dlx3 in mouse embryonic stem cells stimulated Lifr and Chrdl1 expression and inhibited expression of Id proteins and Bmp4. We show that Dlx3 increases the expression of both soluble and transmembrane forms of Lifr. Soluble Lifr may regulate extracellular Lif levels via solution binding, while transmembrane Lifr mediates the signal transduction pathway. The data suggests that Dlx3 may be involved in stem cell differentiation in a dosage dependent way through its interaction with Lifr and with Chrdl1, a known antagonist of Bmp4. We speculate that Dlx3 may also be involved in osteoblast differentiation through interactions involving Lifr, Bmp, and Id proteins and signaling via the JAK/STAT and MAPK pathways. In summary, our data suggests that Dlx3 proteins play a significant role in a highly tuned network in early embryogenesis. Keywords: treated vs.untreated Stable and Transient transfection of Dlx3 in MEF. Total of 4 hybridizations including biological replicates.
2009-08-15 | E-GEOD-11727 | biostudies-arrayexpress
Project description:We report the application of single-molecule-based sequencing technology for anti-LIF therapy on the tumor microenvironment in the immune-component mice.C57 mice were treated with isotype control IgG, anti-LIF, anti-PD-1, or the combination of anti-LIF with anti-PD-1 (combo) individually after subcutaneously injected with PAN02 cells for 5 days. we explored the therapeutic potentials in blocking the LIF-LIFR signaling pathway and confirmed that it can effectively enhance the tumor responsiveness to PD-1 immunotherapy by shifting the T-cells population composition in addition to the inhibition of tumor growth.
2024-12-31 | GSE193121 | GEO
Project description:During bacterial pneumonia, alveolar epithelial cells are critical for maintaining gas exchange and providing antimicrobial as well as pro-immune properties. We previously demonstrated that leukemia inhibitory factor (LIF), an IL-6 family cytokine, is produced by type II alveolar epithelial cells (ATII) and is critical for tissue protection during bacterial pneumonia. However, the target cells and mechanisms of LIF-mediated protection remain unknown. Here, we demonstrate that antibody-induced LIF blockade remodels the lung epithelial transcriptome in association with increased apoptosis. Based on these data, we performed pneumonia studies using a novel mouse model in which LIFR (the unique receptor for LIF) is absent in lung epithelium. While LIFR was detected on the surface of epithelial cells, its absence only minimally contributed to tissue protection during pneumonia. Single-cell RNA-sequencing (scRNAseq) was conducted to identify adult murine lung cell types most prominently expressing LIFR, revealing endothelial cells, mesenchymal cells, and ATIIs as major sources of LIFR. Sequencing data indicated that ATII cells were significantly impacted as a result of pneumonia, with additional differences observed in response to LIF neutralization, including but not limited to gene programs related to cell death, injury, and inflammation. Overall, our data suggest that LIF signaling on epithelial cells alters responses in this cell type during pneumonia. However, our results also suggest separate and perhaps more prominent roles of LIFR in other cell types, such as endothelial cells or mesenchymal cells, which provide grounds for future investigation.
2022-02-17 | GSE179764 | GEO
Project description:All except one cytokine of the Interleukin (IL-)6 family share glycoprotein (gp) 130 as the common b receptor chain. Whereas Interleukin (IL-)11 signal via the non-signaling IL-11 receptor (IL-11R) and gp130 homodimers, leukemia inhibitory factor (LIF) recruits gp130:LIF receptor (LIFR) heterodimers. Using IL-11 as a framework, we exchange the gp130 binding site III of IL-11 with the LIFR binding site III of LIF. The resulting synthetic cytokimera GIL-11 efficiently recruits the non-natural receptor signaling complex consisting of gp130, IL-11R and LIFR resulting in signal transduction and proliferation of factor-depending Ba/F3 cells. Besides LIF and IL-11, GIL-11 does not activate receptor complexes consisting of gp130:LIFR or gp130:IL-11R, respectively. Human GIL-11 shows cross-reactivity to mouse and rescued IL-6R deficient mice following partial hepatectomy, demonstrating gp130:IL-11R:LIFR signaling efficiently induced liver regeneration. With the development of the cytokimera GIL-11, we devise the functional assembly of the non-natural cytokine receptor complex of gp130:IL-11R:LIFR.
2023-04-19 | GSE226064 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) responds poorly to chemotherapeutics due to inherent drug resistance orchestrated by crosstalk between cancer cells and cancer-associated fibroblasts (CAFs). The LIF/LIFR axis activated by this crosstalk contributes significantly to cancer cell stemness and is a potential therapeutic target. Combined targeting of LIFR with small molecular inhibitors along with standard of care remains unexplored.The efficacy of LIFR small molecule inhibitor, EC359 was evaluated in combination with standard-of-care using human and mouse cell lines, tumoroids, KPC (KrasG12D; TP53R172H; Pdx1-Cre), and orthotopically co-implanted murine models. The impact of LIFR targeting on PDAC was analyzed by RNA-sequencing, immunohistochemistry, western blot, and immune profiles by flow cytometry.In co-implantation murine models, EC359 (5mg/kg body weight), in combination with gemcitabine (Gem, 25mg/kg body weight), reduced the tumor burdens up to 90% compared to the untreated controls (p<0.001) and by 55% compared to Gem alone. The RNA-seq analysis of treated tumors showed significant alterations in stemness markers, extracellular matrix modulation, microtubule structure assembly, and adaptive immune response, suggesting the simultaneous targeting of cell-intrinsic and TME-mediated mechanisms by EC359. The EC359 in autochthonous KPC tumors improved the efficacy of Gem and nab-paclitaxel targeting, increased the dendritic cells, but reduced regulatory T-cells, systemically. Mechanistically, EC359 reduces the PDAC cell stemness, stabilizes the microtubule assembly, and reduces the immunosuppressive microenvironment, contributing to improved efficacy of standard of care in PDAC.
2025-08-27 | GSE300401 | GEO
Project description:Dlx3 over-expression in mouse embryonic fibroblasts changed the expression level of numerous genes involved in osteogenesis and embryonic stem cell-related pathways as revealed by microarray analysis. From the list of Dlx3 modulated genes we focused our attention on the study of two candidates, Lifr and Chrdl1. Chromatin immunoprecipitation demonstrated the recruitment of Dlx3 transcription factor to the promoters of Lifr and Chrdl1, and luciferase assays confirmed the role of Dlx3 in the regulation of Lifr expression. Over-expression of Dlx3 in mouse embryonic stem cells stimulated Lifr and Chrdl1 expression and inhibited expression of Id proteins and Bmp4. We show that Dlx3 increases the expression of both soluble and transmembrane forms of Lifr. Soluble Lifr may regulate extracellular Lif levels via solution binding, while transmembrane Lifr mediates the signal transduction pathway. The data suggests that Dlx3 may be involved in stem cell differentiation in a dosage dependent way through its interaction with Lifr and with Chrdl1, a known antagonist of Bmp4. We speculate that Dlx3 may also be involved in osteoblast differentiation through interactions involving Lifr, Bmp, and Id proteins and signaling via the JAK/STAT and MAPK pathways. In summary, our data suggests that Dlx3 proteins play a significant role in a highly tuned network in early embryogenesis. Keywords: treated vs.untreated
2009-08-15 | GSE11727 | GEO