Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA301165 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:TGF-beta is a known driver of epithelial-mesenchymal transition (EMT) which is associated with tumor aggressiveness and metastasis. However, EMT has not been fully explored in clinical specimens of castration-resistant prostate cancer (CRPC) metastases. To assess EMT in CRPC, gene expression analysis was performed on 149 visceral and bone metastases from 62 CRPC patients and immunohistochemical analysis was performed on 185 CRPC bone and visceral metastases from 42 CRPC patients. In addition, to assess the potential of metastases to seed further metastases the mitochondrial genome was sequenced at different metastatic sites in one patient. TGF-beta was increased in bone versus visceral metastases. While primarily cytoplasmic; nuclear and cytoplasmic Twist were significantly higher in bone than in visceral metastases. Slug and Zeb1 were unchanged, with the exception of nuclear Zeb1 being significantly higher in visceral metastases. Importantly, nuclear Twist, Slug, and Zeb1 were only present in a subset of epithelial cells that had an EMT-like phenotype. Underscoring the relevance of EMT-like cells, mitochondrial sequencing revealed that metastases could seed additional metastases in the same patient. In conclusion, while TGF-beta expression and EMT-associated protein expression is present in a considerable number of CRPC visceral and bone metastases, nuclear Twist, Slug, and Zeb1 localization and an EMT-like phenotype (elongated nuclei and cytoplasmic compartment) was only present in a small subset of CRPC bone metastases. Mitochondrial sequencing from different metastases in a CRPC patient provided evidence for the seeding of metastases from previously established metastases, highlighting the biological relevance of EMT-like behavior in CRPC metastases.
2015-12-18 | GSE74685 | GEO
Project description:Epithelial-to-mesenchymal transition (EMT) and cancer stem cells play relevant roles in metastasis and drug resistance in castration-resistant prostate cancer (PCa). Conditioned-media from Cancer-Associated Fibroblasts from two patients with aggressive PCa induce EMT, reversible DNA methylation and transcriptional variations in androgen independent PC3, but not in androgen dependent LN-CaP cells. Focal CpG islands hyper-methylation associated to transcriptional repression of epithelial markers occurs together with widespread hypo-methylation, including promoters of EMT and stemness regulating genes resulting in their transcriptional activation. Remarkably, DNA methylation and transcription patterns are entirely reverted upon exposure to serum-free medium (mesenchymal-to-epithelial transition). DNMT3A is required for de novo methylation and silencing of CDH1 and GRHL2, the ZEB1 direct repressor, while its knock-down prevents EMT entry. These unprecedented results highlight that CAF-released factors induce reversible DNA methylation patterns required for transcriptional variations essential for EMT and stemness in androgen independent PCa cells, suggesting that similar plasticity might occur in tumour microenvironment. This submission contains data and metadata from the methylation profiling by array of PC-3 cells treated with conditioned media from Human prostate fibroblasts (HPFs) and cancer associated fibroblasts (CAFs).
2017-03-03 | E-MTAB-4753 | biostudies-arrayexpress
Project description:Analysis of bone metastases tissue from castration-resistant prostate cancer patients at the RNA level in relation to expression of constitutively active androgen receptor variants termed AR-V7 and AR-V567es.
2011-06-02 | GSE29650 | GEO
Project description:Digitoxin Inhibits Epithelial-to-Mesenchymal-Transition in Hereditary Castration Resistant Prostate Cancer
| PRJNA552274 | ENA
Project description:PI3K (phosphoinositide 3-kinase)/AKT and RAS/MAPK (mitogen-activated protein kinase) pathway coactivation in the prostate epithelium promotes both epithelial–mesenchymal transition (EMT) and metastatic castration-resistant prostate cancer (mCRPC), which is currently incurable. To study the dynamic regulation of the EMT process, we developed novel genetically defined cellular and in vivo model systems from which epithelial, EMT and mesenchymal-like tumor cells with Pten deletion and Kras activation can be isolated. When cultured individually, each population has the capacity to regenerate all three tumor cell populations, indicative of epithelial–mesenchymal plasticity. Despite harboring the same genetic alterations, mesenchymal-like tumor cells are resistant to PI3K and MAPK pathway inhibitors, suggesting that epigenetic mechanisms may regulate the EMT process, as well as dictate the heterogeneous responses of cancer cells to therapy. Among differentially expressed epigenetic regulators, the chromatin remodeling protein HMGA2 is significantly upregulated in EMT and mesenchymal-like tumors cells, as well as in human mCRPC. Knockdown of HMGA2, or suppressing HMGA2 expression with the histone deacetylase inhibitor LBH589, inhibits epithelial–mesenchymal plasticity and stemness activities in vitro and markedly reduces tumor growth and metastasis in vivo through successful targeting of EMT and mesenchymal-like tumor cells. Importantly, LBH589 treatment in combination with castration prevents mCRPC development and significantly prolongs survival following castration by enhancing p53 and androgen receptor acetylation and in turn sensitizing castration-resistant mesenchymal-like tumor cells to androgen deprivation therapy. Taken together, these findings demonstrate that cellular plasticity is regulated epigenetically, and that mesenchymal-like tumor cell populations in mCRPC that are resistant to conventional and targeted therapies can be effectively treated with the epigenetic inhibitor LBH589.
2015-10-12 | GSE67872 | GEO
Project description:PI3K (phosphoinositide 3-kinase)/AKT and RAS/MAPK (mitogen-activated protein kinase) pathway coactivation in the prostate epithelium promotes both epithelial–mesenchymal transition (EMT) and metastatic castration-resistant prostate cancer (mCRPC), which is currently incurable. To study the dynamic regulation of the EMT process, we developed novel genetically defined cellular and in vivo model systems from which epithelial, EMT and mesenchymal-like tumor cells with Pten deletion and Kras activation can be isolated. When cultured individually, each population has the capacity to regenerate all three tumor cell populations, indicative of epithelial–mesenchymal plasticity. Despite harboring the same genetic alterations, mesenchymal-like tumor cells are resistant to PI3K and MAPK pathway inhibitors, suggesting that epigenetic mechanisms may regulate the EMT process, as well as dictate the heterogeneous responses of cancer cells to therapy. Among differentially expressed epigenetic regulators, the chromatin remodeling protein HMGA2 is significantly upregulated in EMT and mesenchymal-like tumors cells, as well as in human mCRPC. Knockdown of HMGA2, or suppressing HMGA2 expression with the histone deacetylase inhibitor LBH589, inhibits epithelial–mesenchymal plasticity and stemness activities in vitro and markedly reduces tumor growth and metastasis in vivo through successful targeting of EMT and mesenchymal-like tumor cells. Importantly, LBH589 treatment in combination with castration prevents mCRPC development and significantly prolongs survival following castration by enhancing p53 and androgen receptor acetylation and in turn sensitizing castration-resistant mesenchymal-like tumor cells to androgen deprivation therapy. Taken together, these findings demonstrate that cellular plasticity is regulated epigenetically, and that mesenchymal-like tumor cell populations in mCRPC that are resistant to conventional and targeted therapies can be effectively treated with the epigenetic inhibitor LBH589.
2015-10-07 | GSE67681 | GEO
Project description:Gene Expression analysis of castration-resistant prostate cancer bone metastases
| PRJNA141237 | ENA
Project description:Epithelial-to-mesenchymal transition (EMT) and cancer stem cells play relevant roles in metastasis and drug resistance in castration-resistant PCa. Conditioned-media from Cancer-Associated Fibroblasts from two patients with aggressive PCa induce EMT, reversible DNA methylation and transcriptional variations in androgen independent PC3, but not in androgen dependent LN-CaP cells. Focal CpG islands hyper-methylation associated to transcriptional repression of epithelial markers occurs together with widespread hypo-methylation, including promoters of EMT and stemness regulating genes resulting in their transcriptional activation. Remarkably, DNA methylation and transcription patterns are entirely reverted upon exposure to serum-free medium (mesenchymal-to-epithelial transition). DNMT3A is required for de novo methylation and silencing of CDH1 and GRHL2, the ZEB1 direct repressor, while its knock-down prevents EMT entry. These unprecedented results highlight that CAF-released factors induce reversible DNA methylation patterns required for transcriptional variations essential for EMT and stemness in androgen independent PCa cells, suggesting that similar plasticity might occur in tumour microenvironment.
2017-03-09 | E-MTAB-4752 | biostudies-arrayexpress
Project description:Analysis of bone metastases tissue from castration-resistant prostate cancer patients at the RNA level in relation to expression of constitutively active androgen receptor variants termed AR-V7 and AR-V567es. Total RNA obtained from frozen bone metastases samples were analyzed using a gene expression array and further to reveal differences in-between sample groups according to expression of AR-V7 and AR-V567es mRNA levels. Samples were defined to have high (AR-V high) or low (others) expression of those variants, respectively, for definition and more information please see Hörnberg et al PLoS One April 2011 Vol 6 Issue 4 , link and PMID below.
2011-06-02 | E-GEOD-29650 | biostudies-arrayexpress
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