Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA107827 | ENA |
REPOSITORIES: ENA
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Project description:Normal human prostate (NHP) epithelial cells undergo senescence in vitro and in vivo, but the underlying molecular mechanisms remain incompletely understood. Here we first show that multiple primary strains of NHP cells are all immunophenotyped as CK5+/CK18+CD44+α2β1+p63+hTERT+ progenitor cells, which gradually lose progenitor markers as they lose proliferative capacity. NHP cell senescence involves loss of telomerase expression, upregulation of p16, and activation of p53. Using genetically defined manipulations of these three signaling pathways, we show that p16 is the primary determinant of the NHP cell proliferative capacity and hTERT is required for unlimited proliferative lifespan. Hence, suppression of 16 alone significantly extends NHP cell lifespan but both p16 inhibition and hTERT are required to immortalize NHP cells. Importantly, the immortalized NHP cells are normal progenitors that possess the ability to differentiate into functional prostatic glands containing both basal and luminal cells and, frequently, neuroendocrine cells. The immortalized NHP cells possess gene expression profiles characteristic of proliferating progenitor cells. Our studies shed light on the molecular mechanisms regulating the proliferative lifespan of NHP progenitor cells and provide direct evidence that basal-like progenitor cells can regenerate the entire prostatic glands in vivo. The availability of these cells should facilitate future studies of prostate cancer development. Further processed data linked below as Supplementary files. TestvsControl: corresponding GSM# 3vs1: GSM266720, 721, 722 4vs1: GSM266727, 730, 731 5vs1: GSM266732, 733, 734 7avs1: GSM266735, 736, 737 9vs1: GSM266772, 773, 812 11vs1: GSM266813, 816, 823 13vs1: GSM266824, 826, 828 Note: The 'TestvsControl' comparisons report the top 100 up- or down-regulated genes. The numeric designations (1 to 13) are used in the corresponding manuscript. The 'SignificantGenes' lists were used in clustering analysis. Keywords: Cell type comparison (senscent and immortalized NHP cells compared to young NHP progenitors)
2008-10-09 | GSE10570 | GEO
Project description:To conduct comparative transcriptomic analyses on normal or malignant prostate epithelial cells in response to tissue contextual changes, we cultured immortalized prostate epithelial cells or prostate cancer cells as cell monolayers or three-dimensional organoids and profiled their transcriptomes in respective culture contexts.
2011-07-03 | GSE30304 | GEO
Project description:To conduct comparative transcriptomic analyses on normal or malignant prostate epithelial cells in response to tissue contextual changes, we cultured immortalized prostate epithelial cells or prostate cancer cells as cell monolayers or three-dimensional organoids and profiled their transcriptomes in respective culture contexts. RWPE-1 (immortalized prostate epithelial cells) and LNCaP cells (prostate cancer cells) were seeded on reconstituted basement membrane (rBM)-coated culture plastics or cultured within three-dimensional (3D) rBM gels. Total RNA samples were collected from cell monolayers or 3D cell clusters (formed at day 2) or acini or spheroids (formed at day 6) in the rBM culture, followed by global gene expression profiling.
2011-07-03 | E-GEOD-30304 | biostudies-arrayexpress
Project description:Elucidating the cell of origin of cancer has great significance in stratifying patients into appropriate treatment groups and for developing novel targeted therapies. Early studies demonstrate that only stem-like basal cells in the normal human prostate (NHP) can function as the cell of origin for prostate cancer (PCa). Here, we show that the organoids derived from bulkNHPluminal cells can also be tumorigenically transformed. We further show that the WIT medium, which is used to culture human mammary epithelial progenitor cells, when combined with the ROCK inhibitor, can readily propagate a population of progenitor-like cells from the primary NHP luminal cell isolates. Such functionally defined luminal progenitors can be transformed by distinct sets of genetic perturbations (i.e., AR+AKT/ERG or c-MYC+PTEN knockout) to form tumor glands. Genome-wide RNA-Seq analysis of freshly purified unperturbed human benign prostatic basal and luminal cells and culture-expanded lineage specific stem/progenitor populations reveals that the luminal progenitors possess a distinct gene expression profile that is greatly enriched in advanced, castration-resistant, and metastatic PCa, and it associates with poor patient survival. The ability of the simple two-dimensional culture system reported herein to greatly enrichNHPprogenitor-like cells should facilitate biological and biochemical studies as well as high-throughput screening in these cells and in progenitor-like PCa cells.
2016-09-25 | GSE74698 | GEO
Project description:Cellular senescence forms a barrier that inhibits the acquisition of an immortal phenotype, a critical feature in tumorigenesis. The inactivation of multiple pathways that positively regulate senescence are required for immortalization. To identify these pathways in an unbiased manner, we performed DNA microarray analyses to assess the expression of 20,000 genes in human prostate epithelial cells (HPECs) passaged to senescence. These gene expression patterns were then compared with those of HPECs immortalized with the human Papillomavirus 16 E7 oncoprotein. Senescent cells display gene expression patterns that reflect their nonproliferative, differentiated phenotype and express secretory proteases and extracellular matrix components. A comparison of genes transcriptionally up-regulated in senescence to those in which expression is significantly down-regulated in immortalized HPECs identified three genes: the chemokine BRAK, DOC1, and a member of the insulin-like growth factor axis, IGFBP-3. Expression of these genes is found to be uniformly lost in human prostate cancer cell lines and xenografts, and previously, their inactivation was documented in tumor samples. Thus, these genes may function in novel pathways that regulate senescence and are inactivated during immortalization. These changes may be critical not only in allowing cells to bypass senescence in vitro but in the progression of prostate cancer in vivo.
2013-01-30 | E-SMDB-6 | biostudies-arrayexpress
Project description:Cellular senescence forms a barrier that inhibits the acquisition of an immortal phenotype, a critical feature in tumorigenesis. The inactivation of multiple pathways that positively regulate senescence are required for immortalization. To identify these pathways in an unbiased manner, we performed DNA microarray analyses to assess the expression of 20,000 genes in human prostate epithelial cells (HPECs) passaged to senescence. These gene expression patterns were then compared with those of HPECs immortalized with the human Papillomavirus 16 E7 oncoprotein. Senescent cells display gene expression patterns that reflect their nonproliferative, differentiated phenotype and express secretory proteases and extracellular matrix components. A comparison of genes transcriptionally up-regulated in senescence to those in which expression is significantly down-regulated in immortalized HPECs identified three genes: the chemokine BRAK, DOC1, and a member of the insulin-like growth factor axis, IGFBP-3. Expression of these genes is found to be uniformly lost in human prostate cancer cell lines and xenografts, and previously, their inactivation was documented in tumor samples. Thus, these genes may function in novel pathways that regulate senescence and are inactivated during immortalization. These changes may be critical not only in allowing cells to bypass senescence in vitro but in the progression of prostate cancer in vivo. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Computed
2005-10-18 | E-GEOD-3460 | biostudies-arrayexpress
Project description:Epithelial senescence, specifically in the bronchiolized regions of the fibrotic lung, is apparent in IPF but not control tissue. In order to better understand the phenotype of these senescent cells we generated a in vitro culture model of senescence utillizing primary normal human bronchial epithelial cells. Cultures were treated with doxorubicin to induce senescence and the transcriptional phenotype of the senescent cultures was compared to DMSO-treated control cultures.
2021-03-08 | GSE166033 | GEO
Project description:The microenvironment of solid tumors is dynamic and frequently contain pockets of low oxygen levels (hypoxia) surrounded by regions of normal oxygen levels. Indeed, a compromised vascular is a is hallmark of the tumor microenvironment, creating gradients of hypoxia. Notably, hypoxia associates with increased metastasis and poor survival in patients. Therefore, to aid therapeutic decisions and better understand hypoxia's role in cancer progression, it is critical to identify endogenous biomarkers of hypoxia to spatially phenotype oncogenic lesions in human tissue, whether precancerous, benign, or malignant. Here, we characterize the glucose transporter GLUT3/SLC2A3 as a biomarker of hypoxia prostate epithelial cells and prostate tumors. Transcriptomic analyses of hypoxic immortalized prostate epithelial cells revealed a highly significant increase in GLUT3 expression. GLUT3 upregulation was also detected by immunostaining in hypoxic prostate epithelial cells and prostate cancer cell lines. Additionally, GLUT3 dramatically co-localized with the hypoxia-marker pimonidazole in xenograft tumors formed from prostate cancer cells and showed distinct concentration gradients within patient-derived xenograft tumors from primary and metastatic prostate cancer. Compared to established hypoxia-response genes, GLUT1 and CA9, GLUT3 shows a higher degree of hypoxia labeling within tumor tissue and may serve as a alternative endogenous biomarker of hypoxia.
2022-02-16 | GSE196634 | GEO
Project description:Pluripotent stem (PS) cells enable the scalable production of tissue-specific derivatives with therapeutic potential for various clinical applications, including muscular dystrophies. Given the similarity to human counterparts, the non-human primate (NHP) is an ideal preclinical model to evaluate several questions, including delivery, biodistribution and immune response. While the generation of human induced PS (iPS) cell-derived myogenic progenitors is well established, there has been no data for NHP counterparts, probably due to the lack of an efficient system to differentiate NHP iPS cells towards the skeletal muscle lineage. Here we report the generation of three independent Macaca fascicularis iPS cell lines and their myogenic differentiation using PAX7 conditional expression. Whole transcriptome analysis confirmed the successful sequential induction of mesoderm, paraxial mesoderm, and myogenic lineages. NHP myogenic progenitors efficiently gave rise to myotubes under appropriate in vitro differentiation conditions and engrafted in vivo into TA muscles of NSG and FKRP-NSG mice. Lastly, we explored the pre-clinical potential of these NHP myogenic progenitors in a single wild-type NHP recipient, demonstrating engraftment and characterizing the interaction with the host immune response. These studies establish an NHP model system in which to study iPS cell-derived myogenic progenitors.
2023-05-03 | GSE228567 | GEO