Translational control of breast cancer plasticity
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE149132 | GEO | 2020/04/27
REPOSITORIES: GEO
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2018-03-09 | PXD006059 | JPOST Repository
Project description:Cancer cell plasticity is an emerging hallmark of the disease where cells can transition into different cellular states, contributing to tumor heterogeneity. Cellular plasticity is linked to cancer progression, treatment resistance, and relapse. Cancer Stem Cells (CSCs) play an important role in cancer cell plasticity, and molecular factors contributing to stemness maintenance are still poorly understood. Here, we investigate the role of XIST (X-inactive specific transcript) long noncoding RNA (lncRNA) in ovarian cancer cellular plasticity. We perform in silico and in vitro analyses to better understand its function. Our findings demonstrate a significant downregulation of XIST in ovarian tumors. cancer patients.Tumors with low XIST expression have higher stemness index and decreased overall survival. This reduction is associated with an increased stemness in tumors with XIST index and decreased overall survival rates. XIST knockdown (KD) in ovarian cancer cell lines increases stem cell population. Transcriptomic data show that low XIST expression correlates with the upregulation of the stem cell-specific pathways MYC and MTOR, as well as the metabolic pathway OXPHO. Our study also demonstrates that XIST KD increases specifically mesenchymal cancer stem cell (MCSC) population. Finally, ovarian cancer cells with XIST KD show higher plasticity under hypoxic conditions by transitioning into Epithelial Cancer Stem CellsCell (ECSC). Our data reveal that XIST loss induces CSC enrichment, leading to higher cellular plasticity. These findings highlight the important role of XIST in protecting cell identity in ovarian cancer and open the door to new therapeutic approaches for patients with low XIST expression
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Project description:MicroRNAs are small regulatory RNAs that post-transcriptionally control gene expression. Reduced expression of DICER, the enzyme involved in microRNA processing, is frequently observed in cancer and is associated with poor clinical outcome in various malignancies. Yet the underlying mechanisms are not well understood. Here, we identify tumor hypoxia as a regulator of DICER expression in large cohorts of breast cancer patients. We show that DICER expression is suppressed by hypoxia through an epigenetic mechanism that involves inhibition of oxygen-dependent H3K27me3 demethylases KDM6A/B and results in silencing of the DICER promoter. Subsequently, reduced miRNA processing leads to derepression of the miR-200 target ZEB1, stimulates the epithelial to mesenchymal transition and ultimately results in the acquisition of stem cell phenotypes in human mammary epithelial cells. Our study uncovers a previously unknown relationship between oxygen-sensitive epigenetic regulators, miRNA biogenesis and tumor stem cell phenotypes that may underlie poor outcome in breast cancer. miRNA profiling of MCF7 cells in normal or hypoxic conditions or after DICER knockdown in MCF7 cells.
2014-09-30 | E-GEOD-61720 | biostudies-arrayexpress
Project description:MicroRNAs are small regulatory RNAs that post-transcriptionally control gene expression. Reduced expression of DICER, the enzyme involved in microRNA processing, is frequently observed in cancer and is associated with poor clinical outcome in various malignancies. Yet the underlying mechanisms are not well understood. Here, we identify tumor hypoxia as a regulator of DICER expression in large cohorts of breast cancer patients. We show that DICER expression is suppressed by hypoxia through an epigenetic mechanism that involves inhibition of oxygen-dependent H3K27me3 demethylases KDM6A/B and results in silencing of the DICER promoter. Subsequently, reduced miRNA processing leads to derepression of the miR-200 target ZEB1, stimulates the epithelial to mesenchymal transition and ultimately results in the acquisition of stem cell phenotypes in human mammary epithelial cells. Our study uncovers a previously unknown relationship between oxygen-sensitive epigenetic regulators, miRNA biogenesis and tumor stem cell phenotypes that may underlie poor outcome in breast cancer. A total of 12 samples were analyzed. For each condition tested, 3 independent experiments were carried out (biological repicates).
2014-09-30 | E-GEOD-61721 | biostudies-arrayexpress
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2014-03-19 | E-GEOD-53925 | biostudies-arrayexpress
Project description:Epithelial cells possess remarkable plasticity, having the ability to become mesenchymal cells through alterations in adhesion and motility (epithelial-to-mesenchymal transition or EMT). Recent studies suggest that EMT endows differentiated epithelial cells with stem cell traits, posing the interesting question of how epithelial plasticity is properly restricted to ensure epithelial differentiation during tissue morphogenesis. Here we identify zinc-finger transcription factor Ovol2 as a key suppressor of EMT of mammary epithelial cells. Epithelia-specific deletion of Ovol2 completely arrests mammary ductal morphogenesis, and depletes epithelial stem/progenitor cell reservoirs. Further, Ovol2-deficient epithelial cells undergo EMT in vivo to become non-epithelial cell types, and that Ovol2 directly represses key EMT inducers such as Zeb1 and regulates stem/progenitor cell responsiveness to TGF-beta. We also provide evidence for a suppressive role of Ovol2 in breast cancer progression. Our findings underscore the critical importance of exquisitely regulating epithelial plasticity to balance stemness with epithelial differentiation in development and cancer. TEBs from control and conditional Ovol2-knockout mammary glands were physically isolated for RNA extraction and hybridization on Affymetrix microarrays. In order to identify primary changes, we analyzed TEBs from 24-25-day-old mice, when morphological differences between control and Ovol2 SSKO were still minimal.
2014-03-19 | E-GEOD-53923 | biostudies-arrayexpress
Project description:To understand the role of the epithelial-to-mesenchymal transition (EMT) and its reverse MET dynamics between health and disease, the identification of epithelial (E)- and mesenchymal (M)-specific genes is essential. The aim of the study was to derive genes that are characteristic E and M phenotypes in breast-derived cells. Their identification can help to understand the functional meaning of their expression and dynamic changes of individual cells, whole cell populations, and tumors, and even patients. Breast cancer stem cells (CSCs) are thought to drive recurrence and metastasis. Their identity has been linked to the epithelial-to-mesenchymal transition (EMT) but remains highly controversial since -- depending on the cell line studied -- either epithelial (E) or mesenchymal (M) markers, alone or together, have been associated with stemness. Using distinct transcript expression signatures characterizing the three different E, M and hybrid E/M cell types, our data support a novel model that links a mixed E/M signature with stemness in 1) individual cells, 2) luminal and basal cell lines, 3) in vivo xenograft mouse models, and 4) in all breast cancer subtypes. In particular, we found that co-expression of E and M signatures was associated with poorest outcome in luminal and basal breast cancer patients, as well as with enrichment for stem-like cells in both E and M breast cell lines. This link between a mixed E/M expression signature and stemness was explained by two findings: first, mixed cultures of E and M cells showed increased cooperation in mammosphere formation (indicative of stemness). Second, single-cell qPCR analysis revealed that E and M genes could be co-expressed in the same cell. These hybrid E/M cells were generated by both E or M cells and had stem-like character since they displayed increased plasticity, produced ALDH1+ progenies self-renewal and mammosphere formation compared to the more differentiated E and M cell types. Thus, the hybrid E/M state reflecting stemness and its promotion by E-M cooperation offers a dual biological rationale for the robust association of the mixed E/M signature with poor prognosis, independent of cellular origin. Together, our model explains previous paradoxical findings that breast CSCs appear to be M in luminal cell lines but E in basal breast cancer cell lines. Our results suggest that targeting E/M heterogeneity by eliminating hybrid E/M cells and cooperation between E and M cell types could improve breast cancer patient survival independent of breast cancer-subtype.
2015-03-17 | GSE66527 | GEO
Project description:Epithelial-to-mesenchymal transition (EMT) is a dynamic process that relies on cellular plasticity; an EMT/MET axis is critical for metastatic colonization of carcinomas. Unlike epithelial programming, regulation of mesenchymal programming is not well understood in EMT. Here we describe the first microRNA that enhances exclusively mesenchymal programming. We demonstrate that microRNA-424 is up-regulated early during a TWIST1/SNAI1-induced EMT, and that it causes cells to express mesenchymal genes without affecting epithelial genes, resulting in a mixed/intermediate EMT. Further, microRNA-424 increases motility, decreases adhesion and induces a growth arrest, changes associated with a complete EMT. Patient microRNA-424 levels positively associate with TWIST1/2 and EMT-like gene signatures and is increased in primary tumors versus matched normal breast. However, microRNA-424 is down-regulated in metastases versus matched primary tumors. Correspondingly, microRNA-424 decreases tumor initiation and is post-transcriptionally down-regulated in macrometastases in mice. RNA-seq identified microRNA-424 regulates numerous genes associated with EMT and breast cancer stemness including the novel miR-424 target, TGFBR3, which regulates mesenchymal phenotypes without influencing miR-424 effects on tumor-initiating phenotypes; instead, we show that ERK signaling is critical for such tumor-initiating effects of miR-424. These findings suggest microRNA-424 plays distinct roles downstream of EMT-inducing factors, facilitating earlier stages, but repressing later stages, of metastasis. Examination of mRNA levels in MCF12A human breast cell lines that stably over-expressed miR-424 or an empty vector (EV) control. Each group has three replicates.
2015-02-26 | E-GEOD-54505 | biostudies-arrayexpress
Project description:The receptor tyrosine kinase AXL is associated with epithelial plasticity in several solid tumors including breast cancer and AXL-targeting agents are currently in clinical trials. We hypothesized that AXL is a driver of stemness traits in cancer by co-option of a regulatory function normally reserved for stem cells. AXL-expressing cells in human mammary epithelial ducts co-expressed markers associated with multipotency, and AXL inhibition abolished colony-formation and self-maintenance activities while promoting terminal differentiation in vitro. Axl-null mice did not exhibit a strong developmental phenotype, but enrichment of Axl+ cells was required for mouse mammary gland reconstitution upon transplantation, and Axl-null mice had reduced incidence of Wnt1-driven mammary tumors. An AXL-dependent gene signature is a feature of transcriptomes in basal breast cancers, and reduced patient survival irrespective of subtype. Our interpretation is that AXL regulates access to epithelial plasticity programs in MaSCs and, when coopted, maintains acquired stemness in breast cancer cells.
2020-08-25 | GSE156662 | GEO