Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

TMPRSS2 Influences Prostate Cancer Metastasis

ABSTRACT: 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.

ORGANISM(S): Mus musculus

SUBMITTER: Ilsa Coleman

PROVIDER: E-GEOD-58822 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis.

Lucas Jared M JM Heinlein Cynthia C Kim Tom T Hernandez Susana A SA Malik Muzdah S MS True Lawrence D LD Morrissey Colm C Corey Eva E Montgomery Bruce B Mostaghel Elahe E Clegg Nigel N Coleman Ilsa I Brown Christopher M CM Schneider Eric L EL Craik Charles C Simon Julian A JA Bedalov Antonio A Nelson Peter S PS

Cancer discovery 20140813 11

<h4>Unlabelled</h4>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 metastases. 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 ident ...[more]

PMID: 25122198

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Project description:Androgen deprivation is the mainstay of therapy for progressive prostate cancer. Despite initial and dramatic tumor inhibition, most men eventually fail therapy and die of metastatic castration-resistant (CR) disease. Here, we characterize the profound degree of genomic alteration found in CR tumors using array CGH, gene expression arrays, and FISH. By cluster analysis, we show that the similarity of the genomic profiles from primary and metastatic tumors is driven by the patient. Using data adjusted for this similarity, we identify numerous high-frequency alterations in the CR tumors, such as 8p loss and chromosome 7 and 8q gain. By integrating array CGH and expression array data, we reveal genes whose correlated values suggest they are relevant to prostate cancer biology. We find alterations that are significantly associated with the metastases of specific organ sites, and others with CR tumors versus the tumors of patients with localized prostate cancer, not treated with androgen deprivation. Within the high-frequency sites of loss in CR metastases, we find an over-representation of genes involved in cellular lipid metabolism, including PTEN. Finally, using FISH we verify the presence of a gene fusion between TMPRSS2 and ERG suggested by chromosome-21 deletions detected by array CGH. We find the fusion in 54% of our CR tumors, and 81% of the fusion-positive tumors contain cells with multiple copies of the fusion. Our investigation lays the foundation for a better understanding of and possible therapeutic targets for CR disease, the poorly responsive and final stage of prostate cancer. The aim of this study was to characterize the genomic changes identified in a set of matched castrate-resistant primary and metastatic prostate cancers. Tumor cells were isolated by laser-capture microdissection from 14 patients, a total of 54 tumor samples. LCM capture samples were isolated from multiple metastastases from all but one patient from whom a single metastasis was available. Primary prostate tumor samples were collected from 12 patients. DNA was amplified by either ligation-mediated PCR (LMP) or WGA (Sigma-Aldrich, St. Louis, MO, USA). Reference DNA was isolated from peripheral blood from a single female individual.

Dataset Information

TMPRSS2 Influences Prostate Cancer Metastasis

Publications

The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis.

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