TMPRSS2 Influences Prostate Cancer Metastasis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE58822 | GEO | 2014/09/09
SECONDARY ACCESSION(S): PRJNA253587
REPOSITORIES: GEO
Similar Datasets
Project description:TMPRSS2 is an androgen-regulated cell surface serine protease expressed predominantly in prostate epithelium. TMPRSS2 is expressed highly in localized high-grade prostate cancers and in the majority of human prostate cancer metastasis. Through the generation of mouse models with a targeted deletion of Tmprss2, we demonstrate that the activity of this protease regulates cancer cell invasion and metastasis to distant organs. By screening combinatorial peptide libraries we identified a spectrum of TMPRSS2 substrates that include pro-hepatocyte growth factor (HGF). HGF activated by TMPRSS2 promoted c-Met receptor tyrosine kinase signaling, and initiated a pro-invasive EMT phenotype. Chemical library screens identified a potent bioavailable TMPRSS2 inhibitor that suppressed prostate cancer metastasis in vivo. Together, these findings provide a mechanistic link between androgen-regulated signaling programs and prostate cancer metastasis that operate via context-dependent interactions with extracellular constituents of the tumor microenvironment. Custom mouse cDNA microarrays were used to measure transcript levels in microdissected anterior prostate tumors from Tmprss2+/+;TRAMP mice, Tmprss2-/-;TRAMP mice or strain-matched benign epithelium. All samples were laser-capture microdissected and total RNA isolated and amplified prior to hybridization against a reference pool of normal adult mouse tissues.
2014-09-09 | E-GEOD-58822 | biostudies-arrayexpress
Project description:Common epithelial cancers are believed to become more aggressive through the accumulation of multiple independent molecular events that lead to the deregulation of cell signaling. However, the discovery that the majority of prostate cancers harbor gene fusions of the 5'-untranslated region of androgen regulated TMPRSS2 promoter with ETS transcription factor family members has brought this paradigm into question1,2. TMPRSS2-ERG gene fusion is the most common molecular sub-type of prostate cancer. Recent work suggests that the TMPRSS2-ERG fusion is associated with a more aggressive clinical phenotype3. In the most advanced castration resistant prostate cancers where the androgen receptor has been inactivated, the TMPRSS2-ERG fusion remains functionally active. Here we show compelling clinical and gene expression data supporting the existence of a TMPRSS2-ERG fusion prostate cancer subclass. Using expression array profiling on 455 primary prostate tumors, we identified an 87 gene expression signature, distinguishing TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity. Computational analysis suggested that this fusion signature was associated with estrogen receptor signaling. Functional studies demonstrated regulation of the TMPRSS2-ERG fusion transcript by estrogenic compounds. These data identify a previously unrecognized mechanism for regulation of the TMPRSS2-ERG, even in the absence of a functional androgen receptor, and thus may have broader implications in the treatment of prostate cancer. Keywords: Prostate cancer, Expression array, Illumina, gene fusion, TMPRSS2, ERG, Signatures, Estrogen Test Cohort: 388 cases from the population based Swedish-Watchful Waiting cohort. The cohort consists of men with localized prostate cancer (clinical stage T1-T2, Mx, N0); Validation cohort: The PhysiciansM-bM-^@M-^Y Health Study (PHS) cohort included 116 US men diagnosed with incidental prostate cancer between 1983 and 2003; 455 cases were annotated for TMPRSS2-ERG fusion. Test Set: GSM208029 ... GSM208392 Validation Set: GSM208404 ... GSM208512
2008-05-27 | E-GEOD-8402 | biostudies-arrayexpress
Project description:Common epithelial cancers are believed to become more aggressive through the accumulation of multiple independent molecular events that lead to the deregulation of cell signaling. However, the discovery that the majority of prostate cancers harbor gene fusions of the 5'-untranslated region of androgen regulated TMPRSS2 promoter with ETS transcription factor family members has brought this paradigm into question1,2. TMPRSS2-ERG gene fusion is the most common molecular sub-type of prostate cancer. Recent work suggests that the TMPRSS2-ERG fusion is associated with a more aggressive clinical phenotype3. In the most advanced castration resistant prostate cancers where the androgen receptor has been inactivated, the TMPRSS2-ERG fusion remains functionally active. Here we show compelling clinical and gene expression data supporting the existence of a TMPRSS2-ERG fusion prostate cancer subclass. Using expression array profiling on 455 primary prostate tumors, we identified an 87 gene expression signature, distinguishing TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity. Computational analysis suggested that this fusion signature was associated with estrogen receptor signaling. Functional studies demonstrated regulation of the TMPRSS2-ERG fusion transcript by estrogenic compounds. These data identify a previously unrecognized mechanism for regulation of the TMPRSS2-ERG, even in the absence of a functional androgen receptor, and thus may have broader implications in the treatment of prostate cancer. Keywords: Prostate cancer, Expression array, Illumina, gene fusion, TMPRSS2, ERG, Signatures, Estrogen
2008-05-28 | GSE8402 | GEO
Project description:Androgen receptor (AR) is a transcription factor that plays a central role in the growth and development of the normal prostate and its malignant transformation. More recently, a majority of prostate cancers have been shown to harbor recurrent gene fusions of the androgen-regulated gene, TMPRSS2, to the oncogenic ETS transcription factor ERG. Here we employed chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-Seq) to explore the genome-wide localization of these transcription factors in human prostate cancer cell lines as well as tissues. Unexpectedly, transcriptional networks emanating from AR and ERG were found to be highly overlapping. Furthermore, AR was found to regulate known 5’ fusion partners in prostate cancer including TMPRSS2, as well as negatively regulating its own expression. While induced by androgen through fusion to TMPRSS2, ERG itself was shown to inhibit AR expression and positively regulate the genomic locus of wild-type ERG, thus revealing multiple levels of molecular cross-talk between AR and ERG. Importantly, androgen-sensitive prostate cancer cells in which ERG is overexpressed are able to proliferate and invade in the absence of androgen. Thus, we dissected the intertwined genomic landscape of two master transcriptional regulators of prostate cancer and suggest a role for ERG in maintaining transcriptional networks necessary for androgen-independent prostate cancer growth. These studies may suggest that future therapies against prostate cancer should target both AR and ERG, rather than AR alone, in order to achieve maximum effectiveness.
2010-05-18 | GSE14092 | GEO
Project description:Androgen receptor (AR) is a transcription factor that plays a central role in the growth and development of the normal prostate and its malignant transformation. More recently, a majority of prostate cancers have been shown to harbor recurrent gene fusions of the androgen-regulated gene, TMPRSS2, to the oncogenic ETS transcription factor ERG. Here we employed chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-Seq) to explore the genome-wide localization of these transcription factors in human prostate cancer cell lines as well as tissues. Unexpectedly, transcriptional networks emanating from AR and ERG were found to be highly overlapping. Furthermore, AR was found to regulate known 5’ fusion partners in prostate cancer including TMPRSS2, as well as negatively regulating its own expression. While induced by androgen through fusion to TMPRSS2, ERG itself was shown to inhibit AR expression and positively regulate the genomic locus of wild-type ERG, thus revealing multiple levels of molecular cross-talk between AR and ERG. Importantly, androgen-sensitive prostate cancer cells in which ERG is overexpressed are able to proliferate and invade in the absence of androgen. Thus, we dissected the intertwined genomic landscape of two master transcriptional regulators of prostate cancer and suggest a role for ERG in maintaining transcriptional networks necessary for androgen-independent prostate cancer growth. These studies may suggest that future therapies against prostate cancer should target both AR and ERG, rather than AR alone, in order to achieve maximum effectiveness. Keywords: Genetic modification
2010-05-18 | GSE14028 | GEO
Project description:Androgen receptor (AR) is a transcription factor that plays a central role in the growth and development of the normal prostate and its malignant transformation. More recently, a majority of prostate cancers have been shown to harbor recurrent gene fusions of the androgen-regulated gene, TMPRSS2, to the oncogenic ETS transcription factor ERG. Here we employed chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-Seq) to explore the genome-wide localization of these transcription factors in human prostate cancer cell lines as well as tissues. Unexpectedly, transcriptional networks emanating from AR and ERG were found to be highly overlapping. Furthermore, AR was found to regulate known 5’ fusion partners in prostate cancer including TMPRSS2, as well as negatively regulating its own expression. While induced by androgen through fusion to TMPRSS2, ERG itself was shown to inhibit AR expression and positively regulate the genomic locus of wild-type ERG, thus revealing multiple levels of molecular cross-talk between AR and ERG. Importantly, androgen-sensitive prostate cancer cells in which ERG is overexpressed are able to proliferate and invade in the absence of androgen. Thus, we dissected the intertwined genomic landscape of two master transcriptional regulators of prostate cancer and suggest a role for ERG in maintaining transcriptional networks necessary for androgen-independent prostate cancer growth. These studies may suggest that future therapies against prostate cancer should target both AR and ERG, rather than AR alone, in order to achieve maximum effectiveness. ChIP_Seq examination of histone modifications and key transcription factors in LNCaP and VCaP prostate cancer cell lines in un-treated, vehicle treated or 10nM R1881 treated conditions. LNCaP ChIP-Seq experiments include samples GSM353609-GSM353618, GSM353625-GSM353628, GSM353633-GSM353635, GSM353641-GSM353644, and GSM353648. VCaP ChIP-Seq experiments include samples GSM353601-GSM353608, GSM353619-GSM353624, GSM353629-GSM353632, and GSM353645-GSM353647. In addition, we performed re-ChIP of AR and ERG in VCaP cells (GSM356767), and examined the effect of ERG knockdown on AR and ERG binding (samples GSM353636-GSM353639). To study ectopic ERG binding we performed ERG ChIP-Seq in stable RWPE+ERG or control cells (samples GSM353649-GSM353650). AR ChIP-Seq was also done in the AR-positive but ETS fusion-negative 22RV1 cells (GSM353640). To further study transcription factor binding and chromatin state we performed ChIP-Seq of AR, ERG, H3K4me3, H3K9me3, H3K27me3 and RNA Pol II in a metastatic prostate tumor tissue (samples GSM353651-GSM353656). To couple the ChIP-Seq experiments with gene expression, we have also done Illumian SAGE-tag profiling in LNCaP cells following androgen treatment for 0, 24 and 48hrs. These DGE experiments correspond to samples GSM353657-GSM353659.
2010-05-17 | E-GEOD-14092 | biostudies-arrayexpress
Project description:The TMPRSS2-ERG fusion positive prostate cancer cell line VCaP was grown for 72h in steroid depleted media (RPMI 10% CDT FBS) prior to vehicle (ethanol) or androgen stimulation (1nM R1881). To allow detailed analysis of androgen regulated gene expression in the VCaP prostate cancer cell line total RNA was harvested every every hour up to 24h using trizol (Sigma), quantified using a Nanodrop spectrophotometer (ND-1000). RNA samples were prepared for analysis on Illumina Human 12 v3 BeadArrays. Raw bead-summary data were generated using GenomeStudio version 1.9.0 (Illumina Inc.). For integrative analysis expression array data were normalised in R using the beadarray software and BASH (see Supplementary Methods for details) (Cairns et al., 2008; Dunning et al., 2007).
2014-12-31 | E-MTAB-2968 | biostudies-arrayexpress
Project description:SARS-CoV-2, the virus responsible for COVID-19, employs two key host proteins to gain entry and replicate within cells, angiotensin-converting enzyme 2 (ACE2) and the cell surface transmembrane protease serine 2 (TMPRSS2). TMPRSS2 was first characterized as an androgen-regulated gene in the prostate. Supporting a role for sex hormones, males relative to females are disproportionately affected by COVID-19 in terms of mortality and morbidity. Several studies, including one employing a large epidemiological cohort, suggested that blocking androgen signaling is protective against COVID-19. Here, we demonstrate that androgens regulate the expression of ACE2, TMPRSS2, and androgen receptor (AR) in subsets of lung epithelial cells. AR levels are markedly elevated in males relative to females greater than 70 years of age. In males greater than 70 years old, smoking was associated with elevated levels of AR and ACE2 in lung epithelial cells. Transcriptional repression of the AR enhancesome with AR or bromodomain and extraterminal domain (BET) antagonists inhibited SARS-CoV-2 infection in vitro. Taken together, these studies support further investigation of transcriptional inhibition of critical host factors in the treatment or prevention of COVID-19. These mouse data are part of a larger investigation (data not provided here) targeting the transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2.
2020-11-30 | GSE159576 | GEO
Project description:The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat due to the lack of effective drugs or vaccines against SARS-CoV-2. The efficacy of several repurposed drugs has been evaluated in clinical trials. Among these drugs, a second second-generation antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry into host cells, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and SARS-CoV-2-infected Ad-ACE2-transduced Tmprss2 knockout (Tmprss2-KO) and wild-type (WT) mice. TMPRSS2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cells, however, such antiviral efficacy of enzalutamide was lacking in human lung cells and organoids. Although Tmprss2 knockout effectively blocked SARS-CoV-2 infection in ACE2-transduced mice, Accordingly, enzalutamide showed no antiviral activity due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19 through reducing TMPRSS2 expression in lung cells.
2020-12-22 | GSE163624 | GEO
Project description:The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat due to the lack of effective drugs or vaccines against SARS-CoV-2. The efficacy of several repurposed drugs has been evaluated in clinical trials. Among these drugs, a second second-generation antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry into host cells, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and SARS-CoV-2-infected Ad-ACE2-transduced Tmprss2 knockout (Tmprss2-KO) and wild-type (WT) mice. TMPRSS2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cells, however, such antiviral efficacy of enzalutamide was lacking in human lung cells and organoids. Although Tmprss2 knockout effectively blocked SARS-CoV-2 infection in ACE2-transduced mice, Accordingly, enzalutamide showed no antiviral activity due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19 through reducing TMPRSS2 expression in lung cells.
2020-12-22 | GSE163623 | GEO