Zeb1-mediated control of PUFA-phospholipids in EMT/plasticity-associated cancer cell ferroptosis
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ABSTRACT:
PROVIDER: PRJNA1103773 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28781384_1.fastq.gz | Fastqsanger.gz | |||
| SRR28781384_2.fastq.gz | Fastqsanger.gz | |||
| SRR28781385_1.fastq.gz | Fastqsanger.gz | |||
| SRR28781385_2.fastq.gz | Fastqsanger.gz | |||
| SRR28781386_1.fastq.gz | Fastqsanger.gz |
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Project description:Therapy resistance and metastasis, the most fatal steps in cancer, are often triggered by a (partial) activation of the epithelial-mesenchymal-transition (EMT)-program. A mesenchymal phenotype predisposes to ferroptosis, a cell death pathway exerted by an iron and oxygen-radical mediated peroxidation of phospholipids containing polyunsaturated fatty acids (PUFAs). We here describe that various forms of EMT-activation, including TGFB-stimulation, increase ferroptosis-susceptibility in cancer cells, which depends on the EMT-transcription factor Zeb1. Among other effects, we demonstrate that Zeb1 increases the ratio of phospholipids containing pro-ferroptotic PUFAs over cyto-protective monounsaturated fatty acids (MUFAs) and modulates the expression of underlying crucial lipogenic enzymes (and ACSL4). Pharmacological inhibition of selected lipogenic enzymes (SCD and FADS2) allows the manipulation of ferroptosis-sensitivity in a Zeb1-dependent manner. Our data are of potential translational relevance and suggest a combination of ferroptosis-activators and SCD-inhibitors for the treatment of aggressive cancers expressing Zeb1, which might also be a useful predictive marker for such a combination therapy
2024-07-05 | GSE264671 | 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: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
Project description:Ferroptosis is a form of regulated cell death driven by the iron-dependent accumulation of oxidized polyunsaturated-fatty-acid-containing phospholipids (PUFA-PLs). Three key molecular features of ferroptosis are peroxidation of PUFA-PLs, accumulation of redox-active ferrous iron, and defective lipid peroxide repair (Dixon and Stockwell, 2019). However, there is currently no reliable way to selectively stain ferroptotic cells in tissue sections to characterize the extent of ferroptosis in animal models of disease and in patient tissue samples. We sought to address this gap by immunizing mice with membranes from lymphoma cells treated with the ferroptosis inducer piperazine erastin (PE), and screening ~4,750 of the resulting monoclonal antibodies generated for their ability to selectively detect cells undergoing ferroptosis. We found that one antibody, termed 3F3 Ferroptotic Membrane Antibody (3F3-FMA), was effective as a selective ferroptosis-staining reagent using immunofluorescence (IF). The antigen of 3F3-FMA was identified by immunoprecipitation and mass spectrometry as the human transferrin receptor 1 protein (TfR1), which imports iron from the extracellular environment into cells. We validated this finding with several additional anti-TfR1 antibodies, and compared them to other potential ferroptosis-detecting reagents via immunofluorescence staining, using fluorescence microscopy and flow cytometry. We found that anti-TfR1 and anti-malondialdehyde (MDA) adduct antibodies were effective at reliably staining ferroptotic tumor cells in numerous cell culture and tissue contexts. In summary, these findings suggest that anti-TfR1 antibodies can be used to selectively label cells undergoing ferroptosis.
2020-03-10 | PXD017425 | Pride
Project description:Depletion of Zeb1 in a KPC-model for pancreatic cancer affected strongly the formation of precursor lesions, tumour grading, invasion and notably metastasis during PDAC progression. In this context, EMT is important for metastasis, but there is variability and specificity (and not redundancy) in the role and function of different EMT-inducing transcription factors.
2017-03-16 | GSE87472 | GEO
Project description:Ferroptosis is a regulated form of necrotic cell death caused by iron-dependent phospholipid peroxidation. It can be induced by inhibiting glutathione peroxidase 4 (GPX4), the key enzyme for efficiently reducing peroxides within phospholipid bilayers. Recent data suggest that cancer cells undergoing EMT (dedifferentiation) and those resistant to standard therapy expose a high vulnerability toward ferroptosis. Although recent studies have begun to identify and characterize the metabolic and genetic determinants underlying ferroptosis, many mechanisms that dictate ferroptosis sensitivity remain unknown. Here, we show that low cell density sensitizes primary mammary epithelial and breast cancer cells to ferroptosis induced by GPX4 inhibition, whereas high cell density confers resistance. These effects occur irrespective of oncogenic signaling, cellular phenotype and expression of the fatty acid ligase acyl-CoA synthetase long chain family member 4 (ACSL4). By contrast, we show that a massive accumulation of neutral triacylglycerides (TAG) enriched with polyunsaturated fatty acids (PUFA) is induced at low cell density. In addition, de novo lipogenesis and desaturation pathways were found to be reduced at low cell density, indicative of increased fatty acid uptake. Our study suggests that PUFA-mediated toxicity is limited by the enrichment in TAGs that in turn might pose a vulnerability towards ferroptosis. Conclusively, cell density regulates lipid metabolism of breast epithelial and cancer cells, which results in a ferroptosis-sensitive cell state with the potential to be exploited therapeutically during metastatic dissemination.
2020-11-13 | PXD016276 | Pride
Project description:Epithelial-mesenchymal transition (EMT) involves profound changes in cell morphology, driven by transcriptional and epigenetic reprogramming. However, it emerges that translation and the ribosome composition play also key role in establishing physio-pathological phenotypes. Using genome-wide analyses, we report significant rearrangement of the translational landscape and machinery during EMT. Specifically, a mesenchymal cell line overexpressing the EMT transcription factor ZEB1 shows alterations in translational reprogramming and fidelity. Considering the change in translational activity of ZEB1-overexpressing mesenchymal cells, including in fidelity activity, we sought for changes in ribosome composition. We thus performed a riboproteome approach, i.e., mass spectrometry (MS)-based quantitative proteomic analysis of purified cytoplasmic ribosomes to highlight any change in relative amount of individual ribosomal proteins between wild-type and ZEB1-overexpressing human mammary epithelial cells.
2024-11-02 | PXD047409 | Pride
Project description:Multiple EMT-promoting/inhibiting transcription factors have been identified including Snail, Zeb1 and Ovol2. To understand differential roles of these factors, we performed gene expression profiling by RNA-seq upon Snail-/Zeb1-induced EMT or Ovol2-induced MET in human mammary epithelial MCF10A cells.
2019-07-01 | GSE70551 | GEO
Project description:Using an in vitro model for malignant transformation of human bronchial epithelial cells (HBECs) we have found epithelial-to-mesenchymal transition (EMT) and expression of the EMT-transcription factor ZEB1 are early and critical events. Specifically, we found preexisting oncogenic mutations in TP53 and KRAS were required for HBECs to engage EMT machinery in response to microenvironmental (serum/TGFβ) or specific oncogenetic (MYC) EMT-inducing factors, which induce EMT through distinct TGFβ-dependent and vitamin D receptor (VDR)-dependent pathways, respectively, with both requiring ZEB1. Functional studies demonstrated ZEB1 causally promotes the malignant progression of HBECs and tumorigenicity of NSCLC and small cell lung cancer (SCLC) lines. Mechanistically ZEB1 directly represses ESRP1 leading to increased mesenchymal splicing of CD44, which drives a switch to CD44hi status and defines a highly transformed subpopulation. This was supported by finding ZEB1 is expressed in early-stage primary non-small cell lung cancers (NSCLC), as early as stage IB tumors, and its expression correlates with TNM stage. We conclude that: ZEB1-induced EMT and associated ESRP1 and CD44 molecular changes are important biomarkers for lung cancer pathogenesis; TGFβ and VDR are EMT chemoprevention targets; and as such, ZEB1 represents an important therapeutic target in NSCLC and SCLC.
2016-08-31 | GSE77925 | GEO
Project description:We investigated the effect of miR-1199-5p, miR-200b-3p and miR-429-3p on gene expression profiles during TGFbeta-induced EMT in normal murine mammary gland cells by using the mRNA-sequencing. Our analysis demonstrates that miR-1199-5p and both miR-200 family members share only 6 target genes, indicating that besides regulating Zeb1 expression they exert distinct functions during EMT.
2017-11-09 | GSE86024 | GEO