Identification of Zeb1 as a single marker for prostate stem cells in the basal cell compartment
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ABSTRACT:
PROVIDER: PRJNA436984 | ENA |
REPOSITORIES: ENA
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Project description:The prostate basal cell compartment is postulated to contain stem/progenitors due to its resistance to castration, capability to differentiation into basal, luminal and neuroendocrine cell lineages of prostate epithelium, and susceptibility to oncogenic transformation. However, the heterogeneity and the interrelationship among different cell subpopulations within prostate basal cells remain largely unknow. Here we find that the core epithelial-to-mesenchymal transition (EMT) inducer Zeb is exclusively expressed in a prostate basal cell subpopulation. The Zeb1+ basal cells are resistant against androgen deprivation, possess greater efficiency to produce prostate spheroids in vitro, undergo self-renewal, and can generate functional prostate with all three cell lineages in vivo at the single cell level. Utilizing unbiased single cell transcriptomic analysis of over 9000 mouse prostate basal cells, we find that Zeb1+ basal cell subset shares gene expression profile with both epithelial and mesenchymal cells and stands out uniquely among all the cell clusters. Pseudotemporal reconstruction revealed three cell lineage trajectories through which the Zeb1+ basal cell subset gives rise to differentiated basal cells, and androgen dependent or independent intermediate cells. at the starting point in the developmental trajectories of cell clusters in prostate basal epithelium. In addition, Zeb1 positive basal cells can be detected in human prostate samples. Our data demonstrate that these Zeb1+ cells are bona fide PSCs in the basal cell compartment. Identification of the prostate stem cell (PSC) and its differentiation path is crucial to advance our understanding of prostate development and tumorigenesis.
2019-03-01 | GSE111429 | GEO
Project description:Immuno-stained (keratin 14+ basal marker) frozen prostate sections were subjected to laser-guided microdissection to isolate basal and luminal epithelial prostate cells for expression profiling. RNA was amplified using the AmpTec TRinucleotide kit (AmpTec GmBH). Expression profiling performed using the Invitrogen post-labelling kit and the CRUK whole genome array (WGA) gene set. Keywords: repeat sample
2008-03-01 | GSE9966 | GEO
Project description:Isolation of prostate stem cells is crucial for understanding their biology during normal development and tumorigenesis. In this aim, we used a transgenic mouse model expressing GFP from the stem cell-specific s-SHIP promoter to mark putative stem cells during postnatal prostate development. We showed that cells identified by s-SHIP/GFP expression are present transiently during early prostate development and localize to the basal cell layer of the epithelium. These prostate s-SHIP/GFP-positive cells represent a subpopulation of the lineage-negative / CD24-positive / Sca-1-positive / CD49f-positive (LSC) cells and are capable of self–renewal together with enhanced growth potential in sphere–forming assay in vitro, a phenotype consistent with that of a prostate stem cell population. Transplantation assays of these prostate GFP-positive cells demonstrate reconstitution of prostate ducts containing both basal and luminal cells in renal grafts. Altogether, these results demonstrate that s-SHIP promoter expression is a new marker for neonatal basal prostate cells exhibiting stem cell properties that enables prostate stem cells in situ identification and isolation via a single consistent parameter. Since the GFP-positive cell population is a small subset of basal LSC cells and is most responsible for stem-like activity, we performed transcriptional profiling of GFP-negative LSC and GFP-positive LSC cells to distinguish a basal cell profile from a tissue stem cell profile.
2016-03-30 | GSE73758 | GEO
Project description:Epithelial-to-mesenchymal transition (EMT) is a fundamental process in development and disease. If aberrantly activated it is a trigger for tumour progression and metastasis (Thiery et al 2009 Cell). It is now known that EMT activation is also associated with the maintenance of stem-cell properties (Mani et al. 2008 Cell). Since Zinc-finger enhancer binding transcription factor 1 (ZEB1) is a crucial EMT activator, we analyzed the changes in the gene expression profile that accompany shRNA mediated loss of ZEB1 in MDA MB 231 basal type breast cancer cells. MDA MB 231 is a cell line that exhibits mesenchymal characteristics, but reverts to an epithelial phenotype upon ZEB1 knock down (Spaderna et al. 2008 Cancer Research). MDA MB 231 cells were stably transfected with control (GFP) or ZEB1 shRNA. Upon puromycin selection, single cell clones were picked and characterized. Cells from two control versus two ZEB1 knockdown clones were harvested, total RNA was isolated and processed to hybridization.
2015-09-15 | E-MTAB-3482 | biostudies-arrayexpress
Project description:Aggressive cancers and normal stem cells often share similar molecular and functional traits. It is unclear if aggressive phenotypes of prostate cancer molecularly resemble normal stem cells residing within the human prostate. We performed high-throughput RNA sequencing on uncultured, highly purified epithelial populations from human prostates obtained after radical prostatectomy. We found the basal population to be defined by genes associated with developmental programs, epigenetic remodeling, and invasiveness. We further generated a 91-gene basal signature and applied it to gene expression datasets from patients with organ-confined or castration-resistant, metastatic prostate cancer. Metastatic prostate cancer was more enriched for the basal stem cell signature than organ-confined prostate cancer. Moreover, histological subtypes within prostate cancer metastases varied in their enrichment of the stem cell signature with small cell neuroendocrine carcinoma being the most stem cell-like. Bioinformatic analysis of the basal cell and two human small cell gene signatures identified a set of E2F target genes common to all three signatures. These results suggest that the most aggressive variants of prostate cancer share a core transcriptional program with normal prostate basal stem cells. Transcriptional analysis of 10 uncultured prostatic basal and luminal populations from either the benign or malignant prostate tissue of 8 human prostate cancer patients by high-throughput RNA-seq
2016-06-01 | E-GEOD-82071 | biostudies-arrayexpress
Project description:The role of Notch signaling in the maintenance and differentiation of adult prostate stem cells remains unclear. We found that Notch ligands are mainly expressed within the basal cell lineage, while active Notch signaling is detected in both the prostate basal and luminal cell lineages. Disrupting the canonical Notch effector RBP-J impairs the differentiation of prostate basal stem cells and increases their proliferation in vitro and in vivo, but does not affect luminal cell biology. Conversely, ectopic Notch activation in adult prostates results in basal cell depletion and luminal cell hyper-proliferation. TGFβ dominates over Notch and overrides Notch ablation-induced proliferation of prostate basal cells. In turn, Notch confers positive feedback by up-regulating a plethora of TGFβ signaling components including TGFβRI. These findings reveal crucial roles of the self-enforced positive reciprocal regulatory loop between TGFβ and Notch in maintaining prostate basal stem cell dormancy. We employed an in vitro prostate sphere assay to further investigate how Notch signaling regulates basal cell proliferation and differentiation. FACS isolated adult murine prostate basal cells (using FVB mice) were cultured in the prostate sphere assay with or without N-[(3,5-Difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine-1,1-dimethylethyl ester (DAPT), an inhibitor for the γ-Secretase complex. Gene expression profiles were taken of vehicle- and DAPT-treated prostate spheres.
2012-11-08 | E-GEOD-34067 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Zinc finger E-box binding protein 1 (ZEB1) and ZEB2 induce epithelial-mesenchymal transition (EMT) and cancer progression. However, little is known about global picture of transcriptional regulation by ZEB1 and ZEB2. Here we identified an inflammatory phenotype regulated by ZEB1 using chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq) in basal type breast cancer cells, followed by gene set enrichment analysis (GSEA) of ZEB1-bound genes.
2017-06-16 | GSE89206 | GEO
Project description:Aggressive cancers and normal stem cells often share similar molecular and functional traits. It is unclear if aggressive phenotypes of prostate cancer molecularly resemble normal stem cells residing within the human prostate. We performed high-throughput RNA sequencing on uncultured, highly purified epithelial populations from human prostates obtained after radical prostatectomy. We found the basal population to be defined by genes associated with developmental programs, epigenetic remodeling, and invasiveness. We further generated a 91-gene basal signature and applied it to gene expression datasets from patients with organ-confined or castration-resistant, metastatic prostate cancer. Metastatic prostate cancer was more enriched for the basal stem cell signature than organ-confined prostate cancer. Moreover, histological subtypes within prostate cancer metastases varied in their enrichment of the stem cell signature with small cell neuroendocrine carcinoma being the most stem cell-like. Bioinformatic analysis of the basal cell and two human small cell gene signatures identified a set of E2F target genes common to all three signatures. These results suggest that the most aggressive variants of prostate cancer share a core transcriptional program with normal prostate basal stem cells.
2016-06-01 | GSE82071 | GEO
Project description:Isolation of prostate stem cells is crucial for understanding their biology during normal development and tumorigenesis. In this aim, we used a transgenic mouse model expressing GFP from the stem cell-specific s-SHIP promoter to mark putative stem cells during postnatal prostate development. We showed that cells identified by s-SHIP/GFP expression are present transiently during early prostate development and localize to the basal cell layer of the epithelium. These prostate s-SHIP/GFP-positive cells represent a subpopulation of the lineage-negative / CD24-positive / Sca-1-positive / CD49f-positive (LSC) cells and are capable of selfârenewal together with enhanced growth potential in sphereâforming assay in vitro, a phenotype consistent with that of a prostate stem cell population. Transplantation assays of these prostate GFP-positive cells demonstrate reconstitution of prostate ducts containing both basal and luminal cells in renal grafts. Altogether, these results demonstrate that s-SHIP promoter expression is a new marker for neonatal basal prostate cells exhibiting stem cell properties that enables prostate stem cells in situ identification and isolation via a single consistent parameter. Since the GFP-positive cell population is a small subset of basal LSC cells and is most responsible for stem-like activity, we performed transcriptional profiling of GFP-negative LSC and GFP-positive LSC cells to distinguish a basal cell profile from a tissue stem cell profile. Prostate tissue was collected from 6-day-old male mice, minced into small fragment, digested with 200 U/ml collagenase IAâS (Sigma; C5894) in Dulbeccoâs modified Eagles medium (DME, Gibco) supplemented with 10% fetal bovine serum (FBS, Hyclone) (DME-10% FBS) at 37°C for 60 min with gentle agitation. The digested cells were filtered through a 40-μm cell strainer (BD Biosciences) washed, and resuspended in DME-10% FBS., filtered and labeled with antibodies against lineage (Ter119, CD31, CD45), CD49f and Sca-1 cell surface markers (Affymetrix ebiosciences). Labeled cells were analyzed and the GFP-negative LSC and GFP-positive-LSC populations were sorted by FACS. For each cell population, 3 independent samples were collected and analysed.
2016-03-30 | E-GEOD-73758 | biostudies-arrayexpress
Project description:The role of Notch signaling in the maintenance and differentiation of adult prostate stem cells remains unclear. We found that Notch ligands are mainly expressed within the basal cell lineage, while active Notch signaling is detected in both the prostate basal and luminal cell lineages. Disrupting the canonical Notch effector RBP-J impairs the differentiation of prostate basal stem cells and increases their proliferation in vitro and in vivo, but does not affect luminal cell biology. Conversely, ectopic Notch activation in adult prostates results in basal cell depletion and luminal cell hyper-proliferation. TGFβ dominates over Notch and overrides Notch ablation-induced proliferation of prostate basal cells. In turn, Notch confers positive feedback by up-regulating a plethora of TGFβ signaling components including TGFβRI. These findings reveal crucial roles of the self-enforced positive reciprocal regulatory loop between TGFβ and Notch in maintaining prostate basal stem cell dormancy.
2012-11-08 | GSE34067 | GEO