RAGE/SNAIL signaling drives Epithelial-Mesenchymal plasticity in metastatic Triple-Negative Breast Cancer
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ABSTRACT:
PROVIDER: PRJNA925438 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23118712_1.fastq.gz | Fastqsanger.gz | |||
| SRR23118712_2.fastq.gz | Fastqsanger.gz | |||
| SRR23118713_1.fastq.gz | Fastqsanger.gz | |||
| SRR23118713_2.fastq.gz | Fastqsanger.gz | |||
| SRR23118714_1.fastq.gz | Fastqsanger.gz |
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Project description:Epithelial-Mesenchymal plasticity plays a fundamental role both in embryogenesis and in tumor cell dissemination during tumor progression. The receptor for advanced glycation end products (RAGE) is a driver of cell plasticity in fibrotic diseases; however, its role and molecular mechanism in triple-negative breast cancer (TNBC) remains unclear. Here, we demonstrate that RAGE signaling maintains the mesenchymal phenotype of aggressive TNBC cells by enforcing the expression of SNAIL. We uncover a crosstalk mechanism between the TGF-β and RAGE pathways that is required for the acquisition of mesenchymal traits in TNBC cells. Consistently, RAGE inhibition elicits epithelial features that block migration and invasion capacities. Since RAGE is a sensor of the tumor microenvironment (TME) and the highly glycolytic rate of tumors induces an acidic TME, we modeled acute acidosis in TNBC cells and showed it promotes enhanced production of RAGE ligands and the activation of RAGE-dependent invasive properties. Furthermore, acute acidosis increases SNAIL levels and tumor cell invasion in a RAGE-dependent manner. Finally, we demonstrate that in vivo inhibition of RAGE reduces metastasis incidence and expands survival, consistent with molecular effects that support the relevance of RAGE signaling in EMT plasticity. These results uncover new molecular insights on the regulation of EMT phenotypes in cancer metastasis and provide rationale for pharmacological intervention of this signaling axis.
2023-12-28 | GSE223229 | GEO
Project description:We tested the preclinical efficacy of two small molecule RAGE inhibitors (TTP488 (Azeliragon) and FPS-ZM1) against TNBC metastasis in the orthotopic xenograft MDA-MB-231/4175 - NSG model. Both TTP488 and FPS-ZM1 impaired TNBC metastasis in this lung metastatic breast cancer model, with TTP488 affecting metastasis to a greater degree than FPS-ZM1. Transcriptomic analysis of the primary tumors revealed that TTP488 and FPS-ZM1 displayed high concordance in gene expression changes affecting metastatic pathways.
2023-06-09 | GSE214268 | GEO
Project description:Cell surface heparan sulfate (HS) plays an essential role in RAGE signaling by inducing RAGE oligomerization. To understand the physiological significance of HS-induced RAGE oligomerization in vivo, we generated RAGE knock-in mice (RageAHA/AHA) by introducing point mutations to specifically disrupt HS–RAGE interaction. The RAGE variant expressed by RageAHA/AHA mice demonstrated normal ligand-binding but greatly impaired capacity of HS-binding and oligomerization. To grasp the full scale of the alteration in gene expression caused by knocking out Rage, we performed a RNAseq analysis of mature neutrophils and lung from WT, RageAHA/AHA and Rage-/- mice. The overall number of differently regulated genes (DEGs) in Rage-/- neutrophils were almost 2.5 times higher than in RageAHA/AHA neutrophils (603 vs. 247). In contrast, the number of DEGs were much less in lungs compared to neutrophils in both strains (202 DEGs in Rage-/- lungs and merely 31 DEGs in RageAHA/AHA lungs), however the difference between the two genotypes was even more dramatic in lungs (7-fold) than we observed in neutrophils (2.5-fold). By comparing transcriptomes of neutrophils and lung tissues from RageAHA/AHA and Rage-/- mice, we present clear evidence that complete deficiency of RAGE had much broader impact on global gene expression compared to point mutations of RAGE.
2021-05-11 | GSE174178 | GEO
Project description:RAGE Inhibitor TTP488 (Azeliragon) Reduces Metastasis in Triple-Negative Breast Cancer
| PRJNA884681 | ENA
Project description:Chronic inflammation promotes cancer progression by affecting the tumor cells and their microenvironment. Here, we demonstrate that the continuous stimulation (6 weeks) of triple-negative breast tumor cells (TNBC) by the potent pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) had a robust effect on gene expression, demonstrating that the cancer cells have been skewed to strong pro-inflammatory phenotype. Moreover, continuous TNFα + IL-1β stimulation has reduced cell-to-cell contacts in the cancer cells and has induced metabolic plasticity in TNBC cells: this was exemplified by increase in active mitochondria area and elevations in the glycolytic as well as mitochondrial respiratory potential of the cancer cells (OXPHOS). Glycolysis has induced p65 activation and has led to increased transcription and expression of pro-metastatic chemokines such as CXCL8, CXCL1 and CCL2 and sICAM-1; agreeing with the ability of these chemokines to induce the recruitment of deleterious myeloid cells to tumors, mainly inhibition of glycolysis has given rise to reduced monocytic cell migration, in vitro and in vivo, in response to cancer cell supernatants obtained following continuous TNFα + IL-1β stimulation. Such inflammation-induced metabolic plasticity, which promotes metastatic cascades in TNBC, may have important clinical implications in the treatment of TNBC patients
2021-05-30 | GSE169017 | GEO
Project description:Chronic inflammation promotes cancer progression by affecting the tumor cells and their microenvironment. Here, we demonstrate that the continuous stimulation (6 weeks) of triple-negative breast tumor cells (TNBC) by the potent pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) had a robust effect on gene expression, demonstrating that the cancer cells have been skewed to strong pro-inflammatory phenotype. Moreover, continuous TNFα + IL-1β stimulation has reduced cell-to-cell contacts in the cancer cells and has induced metabolic plasticity in TNBC cells: this was exemplified by increase in active mitochondria area and elevations in the glycolytic as well as mitochondrial respiratory potential of the cancer cells (OXPHOS). Glycolysis has induced p65 activation and has led to increased transcription and expression of pro-metastatic chemokines such as CXCL8, CXCL1 and CCL2 and sICAM-1; agreeing with the ability of these chemokines to induce the recruitment of deleterious myeloid cells to tumors, mainly inhibition of glycolysis has given rise to reduced monocytic cell migration, in vitro and in vivo, in response to cancer cell supernatants obtained following continuous TNFα + IL-1β stimulation. Such inflammation-induced metabolic plasticity, which promotes metastatic cascades in TNBC, may have important clinical implications in the treatment of TNBC patients
2021-05-30 | GSE169016 | GEO
Project description:To investigate the effect of SNAI1 Knockout on development and growth of triple-negative human breast cancer cells The transcription factor SNAI1 mediates epithelial-mesenchymal transition, fibroblast activation and controls inter-tissue migration. High SNAI1 expression characterizes metastatic triple-negative breast carcinomas, and its knockout by CRISPR/Cas9 uncovered establishment of an epithelio-mesenchymal phenotype accompanied by reduced signaling by the cytokine TGF-β. The SNAI1 knockout cells exhibited plasticity in differentiation, drifting towards the luminal phenotype, gained stemness potential and could differentiate into acinar mammospheres in 3D culture. Loss of SNAI1 derepressed the transcription factor FOXA1, a pioneering factor of mammary luminal progenitors. FOXA1 induced a specific gene program, including the androgen receptor (AR). Inhibiting AR via a specific antagonist regenerated the basal phenotype and blocked acinar differentiation. Thus, loss of SNAI1 in the context of triple-negative breast carcinoma cells promotes an intermediary luminal progenitor phenotype that gains differentiation plasticity, based on the dual transcriptional action of FOXA1 and AR. This function of SNAI1 provides means to separate cell invasiveness from progenitor cell de-differentiation as independent cellular programs.
2022-10-01 | GSE210870 | GEO
Project description:Transcriptional profiling of mouse 4T1 breast cancer cells stably tranduced with pLEX-MCS based lentivirus. Three groups were compared, Vector cells, SNAIL expressing cells; and SNAIL+FBXO11 expressing cells. SNAIL expression induced strong EMT phenotype while SNAIL/FBXO11 reversed cells back to epithelial cells.
2014-12-01 | GSE50887 | GEO
Project description:Plasticity of neoplasia, whereby cancer cells attain stem-cell-like properties, is required for disease progression and represents a major therapeutic challenge. Hypoxia induces breast cancer cell plasticity and stem-cell-like phenotypes. Although this process is poorly understood, reports demonstrate that hypoxia induces the expression of stemness-factors including NANOG, SNAIL and NODAL. Moreover, both stem-cell-like phenotypes and elevated expression of stemness-factors have been linked to metastatic spread and chemoresistance. With the use of high through-put sequencing, we characterized the gene expression profiles of T47D breast cancer cells under normoxic and hypoxic conditions.
2020-04-27 | GSE149132 | GEO
Project description:The multi-ligand Receptor for AGE (RAGE) contributes to atherosclerosis in apolipoprotein (ApoE) null mice in both the non-diabetic and diabetic states. Previous studies using soluble RAGE, the extracellular ligand-binding domain of RAGE, or homozygous RAGE null mice showed that blockade or deletion of RAGE resulted in marked reduction in atherosclerotic lesion area and complexity compared to control animals. In parallel, significant down-regulation of inflammatory mediators and matrix metalloproteinases was evident in ApoE null mice aortas devoid of RAGE compared to those of ApoE null RAGE-expressing mice. Although these findings suggested that RAGE triggered pro-atherogenic mechanisms via regulation of inflammatory gene expression, these studies did not reveal the broader pathways by which RAGE contributed to atherosclerosis in ApoE null mice. Therefore, we performed Affymetrix gene expression arrays on aortas of non-diabetic and diabetic ApoE null mice expressing RAGE or devoid of RAGE at nine weeks of age, as this reflected a time point at which frank atherosclerotic lesions were not yet present, but, that we would be able to identify the genes likely involved in diabetes- and RAGE-dependent atherogenesis. The comparisons were as follows: 1. diabetic ApoE null relative to non-diabetic ApoE null; 2. non-diabetic ApoE null / RAGE null relative to non-diabetic ApoE null; 3. diabetic ApoE null / RAGE null relative to non-diabetic ApoE null / RAGE null; and 4. diabetic ApoE null / RAGE null relative to diabetic ApoE null aorta. Our data reveal that there is very little overlap of the genes which are differentially expressed both in the onset of diabetes in ApoE null mice, and in the effect of RAGE deletion in diabetic ApoE null mice. We next performed a Pathway-Express analysis to determine the pathways that were most associated with the onset of diabetes in ApoE null mice and the effect of RAGE gene deletion in diabetic ApoE null mice. Rigorous statistical analysis was undertaken and revealed that the transforming growth factor-beta pathway (tgf-beta) and focal adhesion pathways might be expected to play a significant role in both the mechanism by which diabetes facilitates the formation of atherosclerotic plaques in ApoE null mice, and the mechanism by which deletion of RAGE ameliorates this effect. We focused on three genes of the tgf-betafamily which were found to be up-regulated in diabetic vs. non-diabetic ApoE null aorta, and which were reduced by deletion of RAGE. These included: thrombospondin1 (Thbs1), transforming growth factor-beta (tgf-beta) and rho-associated kinase (ROCK1). Real-time quantitative polymerase chain reaction and Western blotting experiments were performed, as well as ROCK1 activity assays in mouse aorta, and validated the findings of the Affymetrix gene array. Further, confocal microscopy revealed that a principal cell type in the ApoE null aorta expressing these factors was the vascular smooth muscle cell. Our data suggest the novel finding that the observed reduction of accelerated atherosclerosis in diabetic ApoE null / RAGE null vs. diabetic ApoE null mice occurs, all or in part, through the ROCK1 branch of the TGF-betapathway. We have inferred a detailed mechanism for this process. Taken together, these data suggest that suppression of ROCK1 activity in the atherosclerosis-vulnerable vessel wall, especially in diabetes, but in non-diabetes as well, may underlie the beneficial effects of RAGE antagonism and genetic deletion in murine models. These findings highlight logical and novel targets for therapeutic intervention in cardiovascular disease and diabetes. 1. diabetic ApoE null relative to non-diabetic ApoE null; 2. non-diabetic ApoE null / RAGE null relative to non-diabetic ApoE null; 3. diabetic ApoE null / RAGE null relative to non-diabetic ApoE null / RAGE null; and 4. diabetic ApoE null / RAGE null relative to diabetic ApoE null aorta. There were 4 mice in each group initially. However there are only 3 non-diabetic ApoE null / RAGE null mice in the final experimental sample in group 3 due to a failure to generate cRNA from that sample. All samples were normalized to remove chip-dependent regularities using the RMA method. Chips and controls at each combination of genotype and disease sate were normalized together. The statistical significance of differential expression was calculated using the empirical Bayesian LIMMA (LInear Model for MicroArrays) method A cut-off B>0 was used for the statistical significance of gene expression.
2010-03-07 | E-GEOD-15729 | biostudies-arrayexpress