The small molecule ID8 increases Aldefluor+ breast cancer stem cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE80213 | GEO | 2016/11/01
SECONDARY ACCESSION(S): PRJNA318286
REPOSITORIES: GEO
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Project description:Breast cancer stem cells (bCSCs) have been implicated in tumor progression and therapeutic resistance; however, the molecular mechanisms that define bCSC-state are unclear. We have performed concurrent human miRNome-wide gain- and loss-of-function screens to identify switcher miRNAs controling the choice between bCSC self-renewal and differentiation. These analysis enlightened miR-600 whose silencing resulted in bCSC expansion. Mechanistically, miR-600 targets the stearoyl desaturase 1 (SCD1), an enzyme required to produce active, lipid-modified WNT proteins. To explore further miR-600 interactions and WNT-pathway, SUM159 cell line constructions were made and FACS-sorted to select the bCSCs. We compared gene expression profiles from native, miR-600 'over-expressed', miR-600'knock-down' and siSCD1 bCSCs. We showed that in the absence of miR-600, WNT signaling is maintained active and promotes self-renewal, whereas overexpression of miR-600 inhibits the production of active WNT proteins and promotes bCSC differentiation. These findings highlight a miR-600-centered signaling network that governs bCSC-fate decision and influences tumor progression.
2020-08-25 | E-MTAB-5393 | biostudies-arrayexpress
Project description:Ovarian cancer patients are generally diagnosed at stage III/IV, when ascites is common. The volume of ascites positively correlates with the extent of metastasis and negatively with prognosis. Membrane GRP78, a stress-inducible endoplasmic reticulum chaperone which also appears on the plasma membrane (memGRP78) of aggressive cancers, plays a crucial role in the maintenance of embryonic stem cells. Our present study demonstrates that tumor cells isolated from ascites generated by epithelial ovarian cancer (ID8 cells) bearing mice have increased memGRP78 expression compared to ID8 cells in normal culture. We hypothesize that these ascites associated memGRP78+ cells are cancer stem-like cells (CSC) and memGRP78 is functionally important in CSCs. Supporting this hypothesis, we show that memGRP78+ cells isolated from ascites have increased sphere forming and tumor initiating abilities compared to memGRP78- cells. When the tumor microenvironment is recapitulated by adding ascites fluid to cell culture, ID8 cells express more memGRP78 and increased self-renewing ability compared to those cultured in medium alone. Moreover, compared to their counterparts cultured in normal medium, ID8 cells cultured in ascites, or isolated from ascites, show an increased expression of stem cell markers Sca-1, Snail and SOX9. Importantly, antibodies directed against the carboxy (COOH)-terminal domain of GRP78 significantly reduce the self-renewing ability of murine and human ovarian cancer cells pre-incubated with ascites, associated with a decreased phosphorylation of Akt and GSK3α, and reduced level of the transcriptional factor Snail. Based on this data, we suggest that memGRP78 is a logical therapeutic target for late stage ovarian cancer. Two types of ovarian cancer cells from different organ sites are profiled by gene expression. Parental cells (ID8) and ID8 cells which have metastasized to Ascites (AS).
2015-03-09 | E-GEOD-61285 | biostudies-arrayexpress
Project description:Several human cancers contain a small subpopulation of cells called cancer stem-like cells (CSCs)/cancer initiating cells (CICs), which are defined by the ability of self- renewal, multi-differentiation potential, and tumorigenesis. In current study, we focused on epithelioid sarcoma, which is very rare caner, and isolated CSCs/CICs from epitheloid sarcoma cell line ESX based on ALDH activity using ALDEFLUOR assay towards identification of a new CIC/CSC marker. We performed gene profiling between ALDHhigh and ALDH low cells using cDNA microarray for the identification of good markers of CSCs/CICs of epithelioid sarcoma.
2014-01-07 | E-MEXP-3826 | biostudies-arrayexpress
Project description:Background: Breast cancer stem cells (BCSCs) are considered responsible for cancer relapse and drug-resistance. Understanding the identity of BCSCs may open new avenues in breast cancer therapy. Although several discoveries have been made on BCSCs characterization, the factors critical to BCSCs is largely unclear. This study was aimed to determine whether genomic mutation contributes to the acquisition of cancer stem-like phenotype, and to investigate the genetic and transcriptional features of BCSCs. Methods: We detected the potential mutation hotspot regions by using whole genome sequencing on parental cancer cells and derived serial-generation spheroids in increasing order of BCSC frequency, and then performed target deep DNA sequencing in the level of bulk-cell and single-cell. To identify the transcriptional program associated with BCSCs, bulk-cell and single-cell RNA sequencing were performed. Results: By analyzing whole genome sequencing of bulk cells, potential BCSCs associated mutation hotspot regions were detected. Validation by target deep sequencing, in both bulk-cell and single-cell levels, revealed no genetic changes specifically associated with BCSC phenotype. Moreover, single-cell RNA sequencing showed that cancer cells display profound transcriptional variability at the single-cell level that predicts BCSC features. Notably, this transcriptomic variability is enriched in transcription of a number of genes, revealed as BCSC markers. Individuals with breast cancer in a high-risk recurrence group exhibited higher expression of these transcriptomic variabilities, highlighting their clinical significance. Conclusions: Transcriptional variability, not genetic mutations, distinguish BCSCs from non-BCSCs. The identified BCSCs markers can become novel targets for BCSCs.
2018-10-12 | GSE116180 | GEO
Project description:Ovarian cancer patients are generally diagnosed at stage III/IV, when ascites is common. The volume of ascites positively correlates with the extent of metastasis and negatively with prognosis. Membrane GRP78, a stress-inducible endoplasmic reticulum chaperone which also appears on the plasma membrane (memGRP78) of aggressive cancers, plays a crucial role in the maintenance of embryonic stem cells. Our present study demonstrates that tumor cells isolated from ascites generated by epithelial ovarian cancer (ID8 cells) bearing mice have increased memGRP78 expression compared to ID8 cells in normal culture. We hypothesize that these ascites associated memGRP78+ cells are cancer stem-like cells (CSC) and memGRP78 is functionally important in CSCs. Supporting this hypothesis, we show that memGRP78+ cells isolated from ascites have increased sphere forming and tumor initiating abilities compared to memGRP78- cells. When the tumor microenvironment is recapitulated by adding ascites fluid to cell culture, ID8 cells express more memGRP78 and increased self-renewing ability compared to those cultured in medium alone. Moreover, compared to their counterparts cultured in normal medium, ID8 cells cultured in ascites, or isolated from ascites, show an increased expression of stem cell markers Sca-1, Snail and SOX9. Importantly, antibodies directed against the carboxy (COOH)-terminal domain of GRP78 significantly reduce the self-renewing ability of murine and human ovarian cancer cells pre-incubated with ascites, associated with a decreased phosphorylation of Akt and GSK3α, and reduced level of the transcriptional factor Snail. Based on this data, we suggest that memGRP78 is a logical therapeutic target for late stage ovarian cancer.
2015-03-09 | GSE61285 | GEO
Project description:Self-renewal and differentiation are two epigenetic programs that regulate pluripotency of stem cells. During oncogenesis, dysregulation of these two programs leads to the development of cancer stem cells (CSCs). Here, we used a pan genomic promoter microarray to determine the DNA methylation portrait of breast cancer stem cells (bCSC) compared to non-bCSC
2015-01-01 | E-MTAB-2236 | biostudies-arrayexpress
Project description:It has been suggested that breast cancers are driven and maintained by a cellular subpopulation with stem cell properties. These breast cancer stem cells (BCSCs) mediate metastasis and by virtue of their resistance to radiation and chemotherapy, contribute to relapse. Although several BCSC markers have been described, it is unclear whether these markers identify the same or independent BCSC populations. Based on established breast cancer cell lines, as well as primary tumor samples and xenografts, we show that BCSCs exist in distinct mesenchymal-like (epithelial-mesenchymal transition, EMT) and epithelial-like (mesenchymal-epithelial transition, MET) states characterized by expression of distinct markers, proliferative capacity and invasive characteristics. The gene expression profiles of mesenchymal-like and epithelial-like BCSCs are remarkably similar across the different molecular subtypes of breast cancer and resemble those of distinct basal and luminal stem cells found in the normal breast. We propose that the plasticity of BCSCs allowing them to transition between EMT- and MET-like states endows these cells with the capacity for tissue invasion, dissemination and growth at metastatic sites. Breast cancer cells from patient were sorted using flow cytometry to select for cells that were ALDH+. Gene expression profiles of these cells were compared with profiles of ALDH- cells.
2013-11-14 | E-GEOD-52327 | biostudies-arrayexpress
Project description:With their ability to self-renew and simultaneously fuel the bulk tumor mass with highly proliferative tumor cells, cancer stem cells (CSC) are supposedly driving cancer progression. However, the CSC-phenotype in colorectal cancer (CRC) is unstable and dependent on environmental cues. Since FGF2 is essential for adult and embryonic stem cell culture to maintain self-renewal, we investigated its role in advanced CRC using tumor-derived organoids as experimental model. We found that FGF-Receptor (FGFR) inhibition prevents organoid formation in very early expanding cells but induces cyst formation when applied to already established organoids. Comprehensive transcriptome analyses revealed that the induction of the transcription factor activator protein-1 (AP-1) together with a MAPK stimulation was most prominent after FGFR-inhibition. These effects resemble mechanisms of an acquired resistance against other described tyrosine kinase inhibitors such as targeted therapies against the EGF-Receptor. Furthermore, we detected elevated expression levels of several self-renewal and stemness-associated genes in organoid cultures with active FGF2 signaling. The combined data assumes that CSC are a heterogeneous subpopulation while self-renewal is a common feature regulated by many different pathways. Finally, we highlight the effects of FGF2 signaling as one of numerous aspects of the complex regulation of stemness in cancer.
2020-09-01 | GSE118949 | GEO
Project description:It has been suggested that breast cancers are driven and maintained by a cellular subpopulation with stem cell properties. These breast cancer stem cells (BCSCs) mediate metastasis and by virtue of their resistance to radiation and chemotherapy, contribute to relapse. Although several BCSC markers have been described, it is unclear whether these markers identify the same or independent BCSC populations. Based on established breast cancer cell lines, as well as primary tumor xenografts, we show that BCSCs exist in distinct mesenchymal-like (epithelial-mesenchymal transition, EMT) and epithelial-like (mesenchymal-epithelial transition, MET) states characterized by expression of distinct markers, proliferative capacity and invasive characteristics. The gene expression profiles of mesenchymal-like and epithelial-like BCSCs are remarkably similar across the different molecular subtypes of breast cancer and resemble those of distinct basal and luminal stem cells found in the normal breast. We propose that the plasticity of BCSCs allowing them to transition between EMT- and MET-like states endows these cells with the capacity for tissue invasion, dissemination and growth at metastatic sites. Breast cancer cell lines, primary xenografts and normal breast cells from patient were sorted using flow cytometry to select for cells that were CD24-,CD44+ and ALDH+. Gene expression profiles of CD24-CD44+ cells were compared with non-CD24-CD44+ cells. Gene expression profiles of ALDH+ cells were compared with ALDH- cells.
2013-11-13 | E-GEOD-52262 | biostudies-arrayexpress
Project description:Breast cancer stem cells (BCSCs) are responsible for tumor recurrence and therapy resistance. We have established primary BCSC cultures from human tumors of triple-negative breast cancer (TNBC), a subgroup of breast cancer likely driven by BCSCs. Primary BCSCs generate xenografts phenocopying the tumors of origin, representing a suitable model to investigate breast cancer targeting strategies. In the TNBC cell line MDA-MB-468, we previously screened kinases whose depletion elicited a differentiation response, among which IRAK2 was identified. Since IRAK2 is highly enriched in primary BCSCs we wondered if its depletion could affect their growth. Primary BCSCs and MDA-MB-468 presenting IRAK2 downregulation exhibited decreased proliferation and sphere-forming capacity, evidencing the role of IRAK2 in cellular growth and self-renewal. When transplanted orthotopically into immunocompromised mice, IRAK2 knockdown cells originated smaller xenografts in comparison with control cells, suggesting that IRAK2 downregulation may delay tumor development. Investigating the molecular pathways affected by the knockdown, NF-κB and ERK phosphorylation, IL-6 and cyclin D1 expression, ERN1 signaling and autophagy were decreased in a cell line-dependent way. Transcriptome analysis confirmed that the cells were to some extent differently affected by the knockdown, indicating that their heterogeneity, different mutations, genetic background, expression of IRAK2 and level of its downregulation could influence the outcome of the knockdown. Given that overall IRAK2 downregulation decreased cellular ability to sustain aggressive growth and to endure cellular stress, IRAK2 may be considered an interesting target to compromise TNBC progression, positively contributing to TNBC clinical outcome.
2022-09-15 | GSE213228 | GEO