Dataset Information

The Prospect of Identifying Resistance Mechanisms for Castrate-Resistant Prostate Cancer Using Circulating Tumor Cells: Is Epithelial-to-Mesenchymal Transition a Key Player?

ABSTRACT: Prostate cancer (PCa) is initially driven by excessive androgen receptor (AR) signaling with androgen deprivation therapy (ADT) being a major therapeutic approach to its treatment. However, the development of drug resistance is a significant limitation on the effectiveness of both first-line and more recently developed second-line ADTs. There is a need then to study AR signaling within the context of other oncogenic signaling pathways that likely mediate this resistance. This review focuses on interactions between AR signaling, the well-known phosphatidylinositol-3-kinase/AKT pathway, and an emerging mediator of these pathways, the Hippo/YAP1 axis in metastatic castrate-resistant PCa, and their involvement in the regulation of epithelial-mesenchymal transition (EMT), a feature of disease progression and ADT resistance. Analysis of these pathways in circulating tumor cells (CTCs) may provide an opportunity to evaluate their utility as biomarkers and address their importance in the development of resistance to current ADT with potential to guide future therapies.

SUBMITTER: Khan T

PROVIDER: S-EPMC7149487 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The Prospect of Identifying Resistance Mechanisms for Castrate-Resistant Prostate Cancer Using Circulating Tumor Cells: Is Epithelial-to-Mesenchymal Transition a Key Player?

Khan Tanzila T Scott Kieran F KF Becker Therese M TM Lock John J Nimir Mohammed M Ma Yafeng Y de Souza Paul P

Prostate cancer 20200330

Prostate cancer (PCa) is initially driven by excessive androgen receptor (AR) signaling with androgen deprivation therapy (ADT) being a major therapeutic approach to its treatment. However, the development of drug resistance is a significant limitation on the effectiveness of both first-line and more recently developed second-line ADTs. There is a need then to study AR signaling within the context of other oncogenic signaling pathways that likely mediate this resistance. This review focuses on i ...[more]

PMID: 32292603

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Project description:Epithelial to mesenchymal transition (EMT) is the process by which stationary epithelial cells transdifferentiate to mesenchymal cells with increased motility. EMT is integral in early stages of development and wound healing. Studies have shown that EMT could be a critical early event in tumor metastasis that is involved in acquisition of migratory and invasive properties in multiple carcinomas.In this study, we used 15 published gene expression microarray datasets from Gene Expression Omnibus (GEO) that represent 12 cell lines from 6 cancer types across 95 observations (45 unique samples and 50 replicates) with different modes of induction of EMT or the reverse transition, mesenchymal to epithelial transition (MET). We integrated multiple gene expression datasets while considering study differences, batch effects, and noise in gene expression measurements. A universal differential EMT gene list was obtained by normalizing and correcting the data using four approaches, computing differential expression from each, and identifying a consensus ranking. We confirmed our discovery of novel EMT genes at mRNA and protein levels in an in vitro EMT model of prostate cancer - PC3 epi, EMT and Taxol resistant cell lines. We validate our discovery of C1orf116 as a novel EMT regulator by siRNA knockdown of C1orf116 in PC3 epithelial cells.Among differentially expressed genes, we found known epithelial and mesenchymal marker genes such as CDH1 and ZEB1. Additionally, we discovered genes known in a subset of carcinomas that were unknown in prostate cancer. This included epithelial specific LSR and S100A14 and mesenchymal specific DPYSL3. Furthermore, we also discovered novel EMT genes including a poorly-characterized gene C1orf116. We show that decreased expression of C1orf116 is associated with poor prognosis in lung and prostate cancer patients. We demonstrate that knockdown of C1orf116 expression induced expression of mesenchymal genes in epithelial prostate cancer cell line PC3-epi cells, suggesting it as a candidate driver of the epithelial phenotype.This comprehensive approach of statistical analysis and functional validation identified global expression patterns in EMT and candidate regulatory genes, thereby both extending current knowledge and identifying novel drivers of EMT.

Project description:BackgroundAndrogen deprivation therapies for the hormone-dependent stages of prostate cancer have become so effective that new forms of chemoresistant tumors are emerging in clinical practice, and require new targeted therapies in the metastatic setting. Yet there are important gaps in our understanding of the relevant transcriptional networks driving this process. Progression from localized to metastatic castration resistant prostate cancer (mCRPC) occurs as a result of accumulated resistance mechanisms that develop upon sustained androgen receptor (AR) suppression. Critical to this progression is the plastic nature by which prostate tumor cells transition from epithelial to mesenchymal states (EMT).MethodsHere, using prostate cancer cell lines with different AR composition, we systematically manipulated somatic proteins of the Bromodomain and ExtraTerminal (BET) family (BRD2, BRD3, and BRD4) to determine which BET proteins influence EMT. We used the TCGA repository to correlate the expression of individual BET genes with key EMT genes and determined biochemical recurrence in 414 patients and progression free survival in 488 patients.ResultsWe found that only BRD4-and not BRD2 or BRD3-regulates the expression of SNAI1 and SNAI2, and that the downregulation of these EMT transcription factors significantly increases E-cadherin expression. Furthermore, of the BET genes, only BRD4 correlates with survival outcomes in prostate cancer patients. Moreover, selective degradation of BRD4 protein with MZ1 ablates EMT (transcriptionally and morphologically) induced by TGFß signaling.ConclusionsMany relapsed/refractory tumors share a neuroendocrine transcriptional signature that had been relatively rare until highly successful antiandrogen drugs like abiraterone and enzalutamide came into widespread use. New therapeutic targets must therefore be developed. Our results identify key EMT genes regulated by BRD4, and offers a novel druggable target to treat mCRPC. BRD4-selective protein degraders offer a promising next generation approach to treat the emerging forms of chemoresistance in advanced prostate cancer.

Project description:The most frequent alteration in the prostate oncogenome is loss of chromosome (chr) 8p21 that has been associated with loss of NKX3.1 homeobox gene. Chr8p21 deletions increase significantly with tumor grade and are associated with poor prognosis in prostate cancer (PCa), suggesting critical involvement of this region in tumor progression. Recent studies suggest that apart from NKX3.1, this region harbors alternative tumor suppressors that are yet undefined. We proposed a novel, paradigm shifting hypothesis that this locus is associated with a miRNA gene cluster-miR-3622a/b- that plays a crucial suppressive role in PCa. Here we demonstrate the crucial role of miR-3622a in prostate cancer epithelial-to-mesenchymal transition (EMT). MicroRNA expression profiling in microdissected human PCa clinical tissues showed that miR-3622a expression is widely downregulated and is significantly correlated with poor survival outcome and tumor progression. To understand the functional significance of miR-3622a, knockdown and overexpression was performed using non-transformed prostate epithelial and PCa cell lines, respectively, followed by functional assays. Our data demonstrate that endogenous miR-3622a expression is vital to maintain the epithelial state of normal and untransformed prostate cells. miR-3622a expression inhibits EMT, progression and metastasis of PCa in vitro and in vivo. Further, we found that miR-3622a directly targets EMT effectors ZEB1 and SNAI2. In view of these data, we propose that frequent loss of miR-3622a at chr8p21 region leads to induction of EMT states that in turn, promotes PCa progression and metastasis. This study has potentially significant implications in the field of prostate cancer as it identifies an important miRNA component of a frequently lost chromosomal region with critical roles in prostate carcinogenesis which is a highly significant step towards understanding the mechanistic involvement of this locus. Also, our study indicates that miR-3622a is a novel PCa biomarker and potential drug target for developing therapeutic regimens against advanced PCa.

Dataset Information

The Prospect of Identifying Resistance Mechanisms for Castrate-Resistant Prostate Cancer Using Circulating Tumor Cells: Is Epithelial-to-Mesenchymal Transition a Key Player?

Publications

The Prospect of Identifying Resistance Mechanisms for Castrate-Resistant Prostate Cancer Using Circulating Tumor Cells: Is Epithelial-to-Mesenchymal Transition a Key Player?

Similar Datasets

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