MYC-driven increases in mitochondrial DNA copy number occur early and persist throughout prostatic cancer progression
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PROVIDER: PRJNA1031227 | ENA |
REPOSITORIES: ENA
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Project description:Increased mitochondrial function may render some cancers vulnerable to mitochondrial inhibitors. Since mitochondrial function is regulated partly by mitochondrial DNA copy number (mtDNAcn), accurate measurements of mtDNAcn could help reveal which cancers are driven by increased mitochondrial function and may be candidates for mitochondrial inhibition. However, prior studies have employed bulk macrodissections that fail to account for cell type-specific or tumor cell heterogeneity in mtDNAcn. These studies have often produced unclear results, particularly in prostate cancer. Herein, we developed a multiplex in situ method to spatially quantify cell type specific mtDNAcn. We show that mtDNAcn is increased in luminal cells of high-grade prostatic intraepithelial neoplasia (HGPIN), is increased in prostatic adenocarcinomas (PCa), and is further elevated in metastatic castration-resistant prostate cancer. Increased PCa mtDNAcn was validated by two orthogonal methods and is accompanied by increases in mtRNAs and enzymatic activity. Mechanistically, MYC inhibition in prostate cancer cells decreases mtDNA replication and expression of several mtDNA replication genes, and MYC activation in the mouse prostate leads to increased mtDNA levels in the neoplastic prostate cells. Our in situ approach also revealed elevated mtDNAcn in precancerous lesions of the pancreas and colon/rectum, demonstrating generalization across cancer types using clinical tissue samples.
2024-01-31 | GSE246067 | GEO
Project description:Increased mitochondrial function may render some cancers vulnerable to mitochondrial inhibitors. Since mitochondrial function is regulated partly by mitochondrial DNA copy number (mtDNAcn), accurate measurements of mtDNAcn could help reveal which cancers are driven by increased mitochondrial function and may be candidates for mitochondrial inhibition. However, prior studies have employed bulk macrodissections that fail to account for cell type-specific or tumor cell heterogeneity in mtDNAcn. These studies have often produced unclear results, particularly in prostate cancer. Herein, we developed a multiplex in situ method to spatially quantify cell type specific mtDNAcn. We show that mtDNAcn is increased in luminal cells of high-grade prostatic intraepithelial neoplasia (HGPIN), is increased in prostatic adenocarcinomas (PCa), and is further elevated in metastatic castration-resistant prostate cancer. Increased PCa mtDNAcn was validated by two orthogonal methods and is accompanied by increases in mtRNAs and enzymatic activity. Mechanistically, MYC inhibition in prostate cancer cells decreases mtDNA replication and expression of several mtDNA replication genes, and MYC activation in the mouse prostate leads to increased mtDNA levels in the neoplastic prostate cells. Our in situ approach also revealed elevated mtDNAcn in precancerous lesions of the pancreas and colon/rectum, demonstrating generalization across cancer types using clinical tissue samples.
| S-EPMC9979994 | biostudies-literature
Project description:Increased mitochondrial function may render some cancers vulnerable to mitochondrial inhibitors. Since mitochondrial function is regulated partly by mitochondrial DNA copy number (mtDNAcn), accurate measurements of mtDNAcn could help reveal which cancers are driven by increased mitochondrial function and may be candidates for mitochondrial inhibition. However, prior studies have employed bulk macrodissections that fail to account for cell type-specific or tumor cell heterogeneity in mtDNAcn. These studies have often produced unclear results, particularly in prostate cancer. Herein, we developed a multiplex in situ method to spatially quantify cell type-specific mtDNAcn. We show that mtDNAcn is increased in luminal cells of high-grade prostatic intraepithelial neoplasia (HGPIN), is increased in prostatic adenocarcinomas (PCa), and is further elevated in metastatic castration-resistant prostate cancer. Increased PCa mtDNAcn was validated by 2 orthogonal methods and is accompanied by increases in mtRNAs and enzymatic activity. Mechanistically, MYC inhibition in prostate cancer cells decreases mtDNA replication and expression of several mtDNA replication genes, and MYC activation in the mouse prostate leads to increased mtDNA levels in the neoplastic prostate cells. Our in situ approach also revealed elevated mtDNAcn in precancerous lesions of the pancreas and colon/rectum, demonstrating generalization across cancer types using clinical tissue samples.
| S-EPMC10807718 | biostudies-literature
Project description:Copy number analysis of BPH (Benign Prostatic Hyperplasia)
| PRJNA510968 | ENA
Project description:Analysis of gene expression in prostatic tissue from BPH patients with and without SRD5A2 gene methylation. The hypothesis is that BPH patients with DNA methylation of the SRD5A2 gene promoter have impaired conversion of testosterone to dihydrotestosterone, and therefore may use an alternative signaling pathway for prostatic tissue growth. Here, we compare gene expression profiles of SRD5A2-methylated vs. unmethylated prostatic tissue to nominate alternative biological pathways relevant in each molecular subtype of BPH.
2017-10-01 | GSE101486 | GEO
Project description:Genome wide DNA methylation profiling was done on expressed prostatic secretions (EPS) of normal individuals and dry-core needle biopsy samples of benign and malignant (Primary tumor) prostatic lesions. The Illumina Infinium 850k Infinium MethylationEPIC v 1.0 was used to obtain DNA methylation profiles across approximately 850,000 CpGs in EPS and prostatic lesion biopsy samples. Samples included 4 EPS of normal individuals, and 8 biopsy tissues of benign, and malignant lesions each of patient individuals.
2024-09-02 | GSE241670 | GEO
Project description:Background: The mesenchymal compartment plays a key role in organogenesis and cells within the mesenchyme/stroma are a source of potent molecules that control epithelia during development and tumourigenesis. We have used Serial Analysis of Gene Expression (SAGE) to profile a key subset of prostatic mesenchyme that regulates prostate development and is enriched for growth-regulatory molecules. Results: SAGE libraries were made of prostatic inductive mesenchyme (VMP) and the complete prostatic rudiment (including inductive mesenchyme, epithelium and smooth muscle; VSU). By comparing these two SAGE libraries we generated a list of 219 transcripts that were enriched or specific to inductive mesenchyme and which may act as mesenchymal regulators of organogenesis and tumourigenesis. Conclusions: The use of a precisely defined subset of cells, and a back-comparison approach, allowed us to identify rare mRNAs that might be overlooked using other approaches. Keywords: SAGE, gene profiling
2007-12-21 | GSE7899 | GEO
Project description:Induced pluripotent stem (iPS) cells are a valuable resource for discovery of epigenetic changes critical to cell type-specific differentiation. Although iPS cells have been generated from other terminally differentiated cells, the reprogramming of normal adult human basal prostatic epithelial (E-PZ) cells to a pluripotent state has not been reported. Here, we attempted to reprogram E-PZ cells by forced expression of Oct4, Sox2, c-Myc, and Klf4 using lentiviral vectors and obtained embryonic stem cell (ESC)-like colonies at a frequency of 0.01%. These E-PZ-iPS-like cells with normal karyotype gained expression of pluripotent genes typical of iPS cells (Tra-1-81, SSEA-3, Nanog, Sox2, and Oct4) and lost gene expression characteristic of basal prostatic epithelial cells (CK5, CK14, and p63). E-PZ-iPS-like cells demonstrated pluripotency by differentiating into ectodermal, mesodermal, and endodermal cells in vitro, although lack of teratoma formation in vivo and incomplete demethylation of pluripotency genes suggested only partial reprogramming. Importantly, E-PZ-iPS-like cells re-expressed basal epithelial cell markers (CD44, p63, MAO-A) in response to prostate-specific medium in spheroid culture. Androgen induced expression of androgen receptor (AR), and co-culture with rat urogenital sinus further induced expression of prostate-specific antigen, a hallmark of secretory cells, suggesting that E-PZ-iPS-like cells have the capacity to differentiate into prostatic basal and secretory epithelial cells. Finally, when injected into mice, E-PZ-iPS-like cells expressed basal epithelial cell markers including CD44 and p63. When co-injected with rat urogenital mesenchyme, E-PZ-iPS-like cells expressed AR and expression of p63 and CD44 was repressed. DNA methylation profiling identified key pathways and regulators of prostatic differentiation including Wnt5a, BPM7, PTEN, and NKx3.1 using E-PZ-iPS-lke cells. Our results suggest that iPS-like cells can be derived from prostatic epithelial cells. These cells are pluripotent and capable of prostatic differentiation, and therefore provide a novel model for investigating epigenetic changes involved in prostate cell lineage specification.
2016-01-01 | GSE45469 | GEO
Project description:Background: The mesenchymal compartment plays a key role in organogenesis and cells within the mesenchyme/stroma are a source of potent molecules that control epithelia during development and tumourigenesis. We have used Serial Analysis of Gene Expression (SAGE) to profile a key subset of prostatic mesenchyme that regulates prostate development and is enriched for growth-regulatory molecules. Results: SAGE libraries were made of prostatic inductive mesenchyme (VMP) and the complete prostatic rudiment (including inductive mesenchyme, epithelium and smooth muscle; VSU). By comparing these two SAGE libraries we generated a list of 219 transcripts that were enriched or specific to inductive mesenchyme and which may act as mesenchymal regulators of organogenesis and tumourigenesis. Conclusions: The use of a precisely defined subset of cells, and a back-comparison approach, allowed us to identify rare mRNAs that might be overlooked using other approaches. Keywords: SAGE, gene profiling Two SAGE libraries were prepared and compared to each other. The VMP forms a subset of the VSU.
2007-12-20 | E-GEOD-7899 | biostudies-arrayexpress
Project description:We generated prostatic stromal microarray expression data for functional validation of our LOH/AI hot-/cold-spots in stroma. Stromal cells from normal peripheral zone tissue and from tumors are grown in culture, and were analyed on gene expression platform.
2012-02-27 | GSE34312 | GEO