Pharmacological inhibition of LIFR impairs ovarian cancer progression by blocking LIF/LIFR autocrine loop
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE236743 | GEO | 2024/05/29
REPOSITORIES: GEO
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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:Ferroptosis is a form of regulated cell death characterized by iron-dependent overaccumulation of lipid peroxides. It can be prevented by cellular mechanisms such as GPX4-mediated elimination of the lipid peroxides at the cost of glutathione (GSH). Since originally being discovered as a property of RAS-mutant cancer cells, ferroptosis has been shown to be regulated by several important oncogenes and tumor suppressors. In particular, LIFR, the receptor of the pleiotropic cytokine LIF, has recently been shown to be required for ferroptosis, as loss of Lifr in mouse liver tumor confers the cells resistance to ferroptosis. In this study, however, we found that the LIFR-targeting drugs, EC330 and EC359, are potent inducers of ferroptosis, thus reflecting an interesting “gain-of-function” effect of EC330/EC359 on LIFR-associated ferroptosis. Treatment of various types of cells with EC330/EC359 causes a rapid nonapoptotic cell death with characteristic morphology of ferroptosis, which can be inhibited by iron chelator (DFO) and lipid ROS scavenger (Fer-1), but not pan-caspase inhibitor (z-VAD-fmk). Consistent with previous observations, the efficiency of EC330/EC359 appears to be correlated with the expression levels of LIF and LIFR. RNA-seq analysis showed that the EC330/EC359 treatment leads to (i) a gene expression profile highly resembling that of RSL3, the GPX4-targeting ferroptosis inducer, and (ii) a specific decrease of expression of a few gene encoding membrane-located proteins, especially those located on the mitochondria (e.g., TOMM6 and COX14), implying defects in cellular/mitochondrial membrane functions. Indeed, transmission electron microscopy imaging of the EC330/EC359-treated cells shows shrunken mitochondria and loss of mitochondrial cristae. EC330/EC359 also decreases the activity of GPX4 in the cells to the level comparable with RSL3; meanwhile, the intracellular level of GSH is also decreased, and thus GPX4 inactivation and GSH depletion may jointly disable the cells to eliminate the toxic lipid peroxides. Lastly, although the STAT3 and AKT signaling pathways downstream of LIFR are inhibited by EC330/EC359, inhibition of these pathways per se can only induce non-ferroptotic cell death, suggesting that the EC330/EC359-induced ferroptosis is independent of these downstream pathways; the LIFR-NFkB-LCN2 axis discovered recently in mouse liver tumor cells might not explain the EC330/EC359-induced ferroptosis either, because LCN2 is not detectable in the herein used cell lines. Taken together, these results reveal an unexpected role of the LIFR-targeting drugs EC330/EC359 as potent inducer of ferroptosis and, in combination with previous studies, suggest that there could be either unknown mechanism for the LIFR-associated ferroptosis or unknown target for EC330/EC359 to effect the ferroptosis induction.
2023-07-06 | GSE201493 | GEO
Project description:Pharmacological inhibition of LIFR impairs ovarian cancer progression by blocking LIF/LIFR autocrine loop
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Project description:We examined the transcriptional changes modulated by ESR2 agonist liquiritigenin by perfroming global transcriptome analysis. ES2 cells were treated with either vehicle or liquiritigenin for 24 h and the isolated RNA was utilized for RNA-seq analysis. Our results demonstrated that liquiritigenin modulated several genes that are involved in NF-kB signaling, inflammation, NRF2 mediated oxidative stress response, and MMP signaling.
2017-09-18 | GSE93807 | 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: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
Project description:The LIFR-targeting drugs EC330/EC359 are potent inducers of ferroptosis
| PRJNA831873 | ENA
Project description:In a study using syngeneic BALB/c mice, the impact of a high-fat diet (HFD) on triple-negative breast cancer (TNBC) progression was investigated using 4T1 cells. Mice were fed either a low-fat diet (LFD) or HFD for six weeks before receiving orthotopic injections of 4T1 cells. Post-tumor formation, mice were randomized into three groups: LFD, HFD, and HFD with EC359 treatment. Results indicated that HFD significantly enhanced tumor growth, while EC359 treatment notably reduced HFD-induced TNBC progression. To explore underlying mechanisms, global RNA sequencing was performed on tumor tissues, revealing that HFD altered the expression of 578 genes compared to LFD, with 325 genes differentially expressed between the HFD and HFD + EC359 groups. Gene set enrichment analysis showed that HFD-related genes were linked to cytokine signaling, inflammation, stem cell pathways, TGFβ, metastasis, and epithelial–mesenchymal transition, all of which were downregulated with EC359 treatment.
2024-11-14 | GSE280092 | GEO
Project description:Effects of LIFR inhibition using EC359 on TNBC cells in obesity conditions
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Project description:Leukemia inhibitory factor (LIF), and its receptor (LIFR), are commonly over-expressed in many solid cancers and recent studies have implicated LIF/LIFR axis as a promising clinical target for cancer therapy. LIF/LIFR activate oncogenic signaling pathways including JAK/STAT3 as immediate effectors and MAPK, AKT, mTOR further downstream. LIF/LIFR signaling plays a key role in tumor growth, progression, metastasis, stemness and therapy resistance. Many solid cancers show overexpression of LIF and autocrine stimulation of the LIF/LIFR axis; these are associated with a poorer relapse-free survival. LIF/LIFR signaling also plays a role in modulating multiple immune cell types present in tumor micro environment (TME). Recently, two targeted agents that target LIF (humanized anti-LIF antibody, MSC-1) and LIFR inhibitor (EC359) were under development. Both agents showed effectivity in preclinical models and clinical trials using MSC-1 antibody are in progress. This article reviews the significance of LIF/LIFR pathways and inhibitors that disrupt this process for the treatment of cancer.
| S-EPMC9170604 | biostudies-literature