RAGE/SNAIL signaling drives Epithelial-Mesenchymal plasticity in metastatic Triple-Negative Breast Cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE223229 | GEO | 2023/12/28
REPOSITORIES: GEO
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Project description:Background: Patients with Triple Negative Breast Cancer (TNBC) currently lack targeted therapies, and consequently face higher mortality rates when compared to patients with other breast cancer subtypes. The tumor microenvironment (TME) cytokine Oncostatin M (OSM) reprograms TNBC cells to a more stem-like/mesenchymal state, conferring aggressive cancer cell properties such as enhanced migration and invasion, increased tumor-initiating capacity, and intrinsic resistance to the current standards of care. In contrast to OSM, Interferon-β (IFN-β) promotes a more differentiated, epithelial cell phenotype in addition to its role as an activator of anti-tumor immunity. Importantly, OSM suppresses the production of IFN-β, although the mechanism of IFN-β suppression has not yet been elucidated. Methods: IFN-β production and downstream autocrine signaling were assessed via quantitative real-time PCR (qRT-PCR) and Western blotting in TNBC cells following exposure to OSM. RNA-sequencing (RNA-seq) was used to assess an IFN-β metagene signature, and to assess the expression of innate immune sensors, which are upstream activators of IFN-β. Cell migration was assessed using an in vitro chemotaxis assay. Additionally, TNBC cells were exposed to TGF-β1, Snail, and Zeb1, and IFN-β production and downstream autocrine signaling were assessed via RNA-seq, qRT-PCR, and Western blotting. Results: Here, we identify the repression of Toll-like Receptor 3 (TLR3), an innate immune sensor, as the key molecular event linking OSM signaling and the repression of IFN-β transcription, production, and autocrine IFN signaling. Moreover, we demonstrate that additional epithelial-mesenchymal transition (EMT)-inducing factors, such as TGF-β1, Snail, and Zeb1, similarly suppress TLR3-mediated IFN-β production and signaling. Conclusions: Our findings provide a novel insight into the regulation of TLR3 and IFN-β production in TNBC cells, which are known indicators of treatment responses to DNA-damaging therapies. Furthermore, strategies to stimulate TLR3 in order to increase IFN-β within the TME may be ineffective in stem-like/mesenchymal cells, as TLR3 is strongly repressed. Rather, we propose that therapies targeting OSM or OSM receptor (OSMR) would reverse the stem-like/mesenchymal program and restore TLR3-mediated IFN-β production within the TME, facilitating improved responses to current therapies.
2024-11-25 | GSE282447 | GEO
Project description:Epithelial-mesenchymal transition (EMT) is in the highlights as a significant role in tumor progression and invasion. Snail was known as the one of regulators of EMT in various malignant tumors. The aim of this study was to investigate the effect of Snail on invasiveness/migratory ability of gastric cancer cell lines and clinicopathological and prognostic significance of Snail over-expression using immunohistochemistry in tissue microarray of 314 gastric adenocarcinomas (GC). Differential gene expression in Snail over-expressed GC was investigated using cDNA microarray analysis. Silencing of Snail by ShRNA induced decreased of invasion, migration of gastric cancer cell lines. In contrast, over-expression of Snail induced increased invasiveness and migratory ability of gastric cancer cell lines in accordance increase of VEGF and MMP11. Furthermore, the over-expression of Snail (?75% nuclear staining of Snail) was significantly associated with tumor progression (p<0.0001), lymph node metastases (p=0.002), lymphovascular invasion (p=0.002), and perineural invasion (p=0.002) in 314 GC patient. Snail over-expression was also associated with poor prognosis (shorter survival) in GC patients (p=0.023). cDNA microarray revealed 213 differential expressed genes in Snail over-expressed GC tissues, including genes related to metastasis, invasion. Based on above results, it was suggested that Snail plays a significant role in invasiveness/migratory ability of GCs. In addition, Snail might be used to predictive biomarker for evaluation of prognosis or aggressiveness in GCs. 48 primary gastric adenocarcinoma fresh frozen tissues were used for microarray. All the tissues were obtained after curative resection after pathologic confirm at Pusan National University Hospital (PNUH, Busan, Korea) and Cheonnam University Hospital (CNUH, Cheonnam, Korea). Microarray experiment and data analysis were done at Cancer research institute, PNUH, Busan, Korea.
2012-05-17 | E-GEOD-38024 | biostudies-arrayexpress
Project description:Epithelial-mesenchymal transition (EMT) is in the highlights as a significant role in tumor progression and invasion. Snail was known as the one of regulators of EMT in various malignant tumors. The aim of this study was to investigate the effect of Snail on invasiveness/migratory ability of gastric cancer cell lines and clinicopathological and prognostic significance of Snail over-expression using immunohistochemistry in tissue microarray of 314 gastric adenocarcinomas (GC). Differential gene expression in Snail over-expressed GC was investigated using cDNA microarray analysis. Silencing of Snail by ShRNA induced decreased of invasion, migration of gastric cancer cell lines. In contrast, over-expression of Snail induced increased invasiveness and migratory ability of gastric cancer cell lines in accordance increase of VEGF and MMP11. Furthermore, the over-expression of Snail (≥75% nuclear staining of Snail) was significantly associated with tumor progression (p<0.0001), lymph node metastases (p=0.002), lymphovascular invasion (p=0.002), and perineural invasion (p=0.002) in 314 GC patient. Snail over-expression was also associated with poor prognosis (shorter survival) in GC patients (p=0.023). cDNA microarray revealed 213 differential expressed genes in Snail over-expressed GC tissues, including genes related to metastasis, invasion. Based on above results, it was suggested that Snail plays a significant role in invasiveness/migratory ability of GCs. In addition, Snail might be used to predictive biomarker for evaluation of prognosis or aggressiveness in GCs.
2012-05-18 | GSE38024 | GEO
Project description:Cell plasticity is emerging as a key regulator of tumor progression and metastasis. During carcinoma dissemination epithelial cells undergo epithelial to mesenchymal transition (EMT) processes characterized by the acquisition of migratory/invasive properties, while the reverse, mesenchymal to epithelial transition (MET) process, is also essential for metastasis outgrowth. Different transcription factors, called EMT-TFs, including Snail, bHLH and Zeb families are drivers of the EMT branch of epithelial plasticity, and can be post-transcriptionally downregulated by several miRNAs, as the miR-200 family. The specific or redundant role of different EMT-TFs and their functional interrelations are not fully understood. To study the interplay between different EMT-TFs, comprehensive gain and loss-of-function studies of Snail1, Snail2 and/or Zeb1 factors were performed in the prototypical MDCK cell model system. We here describe that Snail1 and Zeb1 are mutually required for EMT induction while continuous Snail1 and Snail2 expression, but not Zeb1, is needed for maintenance of the mesenchymal phenotype in MDCK cells. In this model system, EMT is coordinated by Snail1 and Zeb1 through transcriptional and epigenetic downregulation of the miR-200 family. Interestingly, Snail1 is involved in epigenetic CpG DNA methylation of the miR-200 loci, essential to maintain the mesenchymal phenotype. The present results thus define a novel functional interplay between Snail and Zeb EMT-TFs in miR200f regulation providing a molecular link to their previous involvement in the generation of EMT process in vivo. Expression analysis of MDCK over-expression EMT-TF Analysis of 7 overexpression MDCK cells each of them using biological rpelicates (MDCK-E47, Snail2, Snail1, Twist1, Tiwst2, Zeb1, Zeb2)
2014-09-09 | E-GEOD-61217 | biostudies-arrayexpress
Project description:To screen the genes regulated by wt-Snail and non-acetylated Snail The successful development of cancer metastasis requires two major events: the reprogramming of cancer cells to increase their migration and tumor-initiation capabilities; and the remodeling of the tumor microenvironment to facilitate invasion and colonization of cancer cells. Epithelial-mesenchymal transition (EMT) is a crucial mechanism for reprogramming cancer cells to possess tumor initiation and migration capabilities1,2. However, the role of EMT in the interplay between tumor and host cells is largely unknown. The EMT regulator Snail is mainly known as a transcriptional repressor of the adhesion protein E-cadherin, whose repression is considered to be a key step in initiating metastasis3,4. We previously found that Snail can also act as an activator that induces the transcription of ERCC15 and IL86. Here we show that Snail is acetylated by CREB-binding protein (CBP) and that Snail and CBP co-occupy the promoters of target genes to activate transcription of the target genes. Furthermore, Snail activates the expression of a panel of cytokine genes, including TNFa (which forms a positive feedback loop with Snail to amplify the signal) and CCL2 and CCL5 (which facilitate the recruitment of macrophages by cancer cells). Our results demonstrate a novel function for Snail, providing new understanding of the recruitment of host cells to tumor sites during metastatic evolution. Establish stable transfectants of pCDH-Snail and pCDH-Snail2R in FaDu cells and analyze the mRNA expression level of by cDNA microarray. FaDu transfected with pCDH vector was used as a control experiment.
2014-08-16 | E-GEOD-58592 | biostudies-arrayexpress
Project description:To screen the genes regulated by wt-Snail and non-acetylated Snail The successful development of cancer metastasis requires two major events: the reprogramming of cancer cells to increase their migration and tumor-initiation capabilities; and the remodeling of the tumor microenvironment to facilitate invasion and colonization of cancer cells. Epithelial-mesenchymal transition (EMT) is a crucial mechanism for reprogramming cancer cells to possess tumor initiation and migration capabilities1,2. However, the role of EMT in the interplay between tumor and host cells is largely unknown. The EMT regulator Snail is mainly known as a transcriptional repressor of the adhesion protein E-cadherin, whose repression is considered to be a key step in initiating metastasis3,4. We previously found that Snail can also act as an activator that induces the transcription of ERCC15 and IL86. Here we show that Snail is acetylated by CREB-binding protein (CBP) and that Snail and CBP co-occupy the promoters of target genes to activate transcription of the target genes. Furthermore, Snail activates the expression of a panel of cytokine genes, including TNFa (which forms a positive feedback loop with Snail to amplify the signal) and CCL2 and CCL5 (which facilitate the recruitment of macrophages by cancer cells). Our results demonstrate a novel function for Snail, providing new understanding of the recruitment of host cells to tumor sites during metastatic evolution.
2014-08-16 | GSE58592 | GEO
Project description:The epithelial-to-mesenchymal transition (EMT) is a critical biological process in normal development and tumor progression. One of the EMT regulator, Snail is shown to suppress or activate its downstream genes to sustain migratory capacities while remodeling the tumor microenvironment. Identification of the Snail-regulated transcriptome through a robust sequencing technique will give a global direction for targeting Snail-driven malignancy.
2017-01-04 | GSE65131 | GEO
Project description:Dynamic regulation of glucose flux between aerobic glycolysis and the pentose phosphate pathway (PPP) during epithelial-mesenchymal transition (EMT) is not well-understood. Here we show that Snail (SNAI1), a key transcriptional repressor of EMT, regulates glucose flux toward PPP, allowing cancer cell survival under metabolic stress. Mechanistically, Snail regulates glycolytic activity via repression of PFKP (phosphofructokinase, platelet), a major isoform of cancer-specific phosphofructokinase-1 (PFK-1), an enzyme involving the first rate-limiting step of glycolysis. The suppression of PFKP switches the glucose flux towards PPP, generating NADPH with increased metabolites of oxidative PPP. Functionally, dynamic regulation of PFKP significantly potentiates cancer cell survival under metabolic stress and increases metastatic capacities in vivo. Further, knockdown of PFKP rescues metabolic reprogramming and cell death induced by loss of Snail. Thus, the Snail-PFKP axis plays an important role in cancer cell survival via regulation of glucose flux between glycolysis and PPP.Dynamic regulation of glucose flux between aerobic glycolysis and the pentose phosphate pathway (PPP) during epithelial-mesenchymal transition (EMT) is not well-understood. Here we show that Snail (SNAI1), a key transcriptional repressor of EMT, regulates glucose flux toward PPP, allowing cancer cell survival under metabolic stress. Mechanistically, Snail regulates glycolytic activity via repression of PFKP (phosphofructokinase, platelet), a major isoform of cancer-specific phosphofructokinase-1 (PFK-1), an enzyme involving the first rate-limiting step of glycolysis. The suppression of PFKP switches the glucose flux towards PPP, generating NADPH with increased metabolites of oxidative PPP. Functionally, dynamic regulation of PFKP significantly potentiates cancer cell survival under metabolic stress and increases metastatic capacities in vivo. Further, knockdown of PFKP rescues metabolic reprogramming and cell death induced by loss of Snail. Thus, the Snail-PFKP axis plays an important role in cancer cell survival via regulation of glucose flux between glycolysis and PPP.
2017-11-07 | MTBLS387 | MetaboLights
Project description:A variety of mechanotransduction forces are altered in the tumor microenvironment (TME) and these biophysical forces can influence cancer progression. One such force is interstitial fluid flow (IFF) - the movement of fluid through the tissue matrix. IFF was previously shown to induce invasion of cancer cells, but the activated signaling cascades remain poorly understood. Here, it is demonstrated that IFF induces invasion of ERBB2/HER2 expressing breast cancer cells via activation of phosphoinositide-3-kinase (PI3K). In constitutively activate ERBB2 expressing cells that have undergone epithelial-to-mesenchymal transition (EMT), IFF-mediated invasion requires the chemokine receptor CXCR4, a gradient of its ligand CXCL12, and activity of the PI3K catalytic subunits p110a and ?. In wild-type ERBB2 expressing cells, IFF-mediated invasion is chemokine receptor-independent and requires only p110a activation. To test whether cells undergoing EMT alter their signaling response to IFF, TGFb1 was used to induce EMT in wild-type ERBB2-expressing cells resulting in IFF-induced invasion dependent on CXCR4 and p110?. 2 cell lines (NeuN, NeuT), 2 conditions (flow, static), 3 replicates each, 12 samples total
2015-01-06 | E-GEOD-64670 | biostudies-arrayexpress
Project description:Cell plasticity is emerging as a key regulator of tumor progression and metastasis. During carcinoma dissemination epithelial cells undergo epithelial to mesenchymal transition (EMT) processes characterized by the acquisition of migratory/invasive properties, while the reverse, mesenchymal to epithelial transition (MET) process, is also essential for metastasis outgrowth. Different transcription factors, called EMT-TFs, including Snail, bHLH and Zeb families are drivers of the EMT branch of epithelial plasticity, and can be post-transcriptionally downregulated by several miRNAs, as the miR-200 family. The specific or redundant role of different EMT-TFs and their functional interrelations are not fully understood. To study the interplay between different EMT-TFs, comprehensive gain and loss-of-function studies of Snail1, Snail2 and/or Zeb1 factors were performed in the prototypical MDCK cell model system. We here describe that Snail1 and Zeb1 are mutually required for EMT induction while continuous Snail1 and Snail2 expression, but not Zeb1, is needed for maintenance of the mesenchymal phenotype in MDCK cells. In this model system, EMT is coordinated by Snail1 and Zeb1 through transcriptional and epigenetic downregulation of the miR-200 family. Interestingly, Snail1 is involved in epigenetic CpG DNA methylation of the miR-200 loci, essential to maintain the mesenchymal phenotype. The present results thus define a novel functional interplay between Snail and Zeb EMT-TFs in miR200f regulation providing a molecular link to their previous involvement in the generation of EMT process in vivo. Expression analysis of MDCK over-expression EMT-TF
2014-09-09 | GSE61217 | GEO