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Identification of a gene expression signature associated with the metastasis suppressor function of NME1

ABSTRACT: Transciptome analysis using a panel of WM793 melanoma cell lines following stable overexpression of wild-type or mutant forms of human NME1 NME1 is well known for its ability to suppress melanoma metastasis, however the means by which NME1 accomplishes this remains controversial. Herein, we utilized a bioinformatics approach to systematically identify effector genes of NME1’s metastasis suppressor function by tracking genes regulated by wild-type NME1 but not by metastasis suppressor deficient mutants of NME1. This approach identified a number of novel genes, such as ALDOC, CXCL11, LRP1b and XAGE1 as well as known targets of NME1 such as NETO2. Our NME1-mediated Metastasis Suppressor Signature (MSS) was capable of identifying subpopulations of metastatic melanoma patients with prolonged progression free survival. Interestingly, when patients were clustered by an extension of the MSS, two populations of metastatic melanoma patients were identified with significantly lowered overall and progression free survival times. Together, these data demonstrate that NMEl is a powerful tool for identifying genes that both promote and inhibit melanoma metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE85978 | GEO | 2017/08/22

SECONDARY ACCESSION(S): PRJNA339922

REPOSITORIES: GEO

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Comprehensive molecular profiling of UV-induced metastatic melanoma in Nme1/Nme2-deficient mice reveals novel genes associated with progression and survival in human patients

Project description:Purpose: Herein we demonstrate that UV-induced melanomas of low metastatic potential in mice that overexpress HGF and harbor deletion of the Ink4a/p16 locus (HP strain) are converted to highly metastatic forms by virtue of hemizygous deletion of the metastasis suppressor genes Nme1 and Nme2 (HPN strain). The striking difference in metastatic activity between HP and HPN melanomas strains provided a powerful system for identifying molecular profiles associated with metastatic activity. Methods: Primary and metastatic melanoma RNAseq profiling. Results: RNA-seq analysis of primary melanomas identified a 32-gene expression signature that was strongly associated with the HPN genotype and lung metastatic activity (HPN lung metastasis signature, or HPN-LMS). Expression of the HPN-LMS was highly predictive of overall survival in human cohorts of cutaneous melanoma (SKCM) and uveal melanoma (UVM) patients of The Cancer Genome Atlas (TCGA). Conclusions: Three HPN-LMS genes (ARRDC3, NYNRIN, RND3) associated with longer survival in SKCM and/or UVM patients exhibited strong anti-invasion activity in human melanoma cells, consistent with roles as effectors of the metastasis suppressor functions of Nme1 and Nme2. The HP/HPN mouse paradigm has thus yielded a network of potential therapeutic targets and prognostic markers for clinical management of metastatic melanoma.

2021-08-02 | GSE181207 | GEO

Identification and Validation of Genes with Expression Patterns Inverse to Multiple Metastasis Suppressor Genes in Breast Cancer Cell Lines

Project description:Metastasis suppressor genes (MSGs) have contributed to an understanding of regulatory pathways unique to the lethal metastatic process. When re-expressed in experimental models, MSGs block cancer spread to, and colonization of distant sites without affecting primary tumor formation. On a single MSG basis, genes have been identified with expression patterns inverse to a MSG, and found to encode functional, druggable signaling pathways. We now hypothesize that common signaling pathways mediate the effects of many MSGs. By gene expression profiling of human MCF7 breast carcinoma cells expressing a scrambled siRNA or siRNAs to each of 19 validated MSGs (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1), we identified genes whose expression was significantly opposite to at least five MSGs. We used microarrays to evaluate the modification in gene expression profile after donregulation of multiple metastasis suppressors (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1) in the breast cancer cell line, MCF7. MCF7 cell line was transfected with siRNA targeting each of 19 metastasis suppressors (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1). Two siRNA sequences (siRNA1 and siRNA2) were used for each metastasis suppressor. Two time points (48hr and 96hr) were considered as end of transfection in order to measure early and late effects of the metastasis suppressors downregulation.

2013-12-27 | E-GEOD-53668 | biostudies-arrayexpress

Integrated Assessment of Circulating Cell-Free MicroRNA Signatures in Plasma of Patients with Melanoma Brain Metastasis

Project description:We analyzed cell-free microRNAs (cfmiRs) in blood, tissue, and urine samples of melanoma patients to find potential biomarkers for monitoring and assessing early detection of melanoma metastasis. This study demonstrates that identifying cfmiR signatures in body fluids may allow for detection and assessment of melanoma brain metastasis (MBM) and metastatic melanoma patients undergoing checkpoint inhibitor immunotherapy treatments.

2020-07-15 | GSE150956 | GEO

PTEN phosphatase inhibits metastasis

Project description:PTEN encodes a tumor suppressor with lipid and protein phosphatase activities whose dysfunction has been implicated in melanomagenesis; less is known about how its phosphatases regulate melanoma metastasis. We show that PTEN expression negatively correlates with metastatic progression in human melanoma samples and a PTEN-deficient mouse melanoma model. Wildtype PTEN expression inhibited melanoma cell invasiveness and metastasis in a dose-dependent manner, behaviors that specifically required PTEN protein phosphatase activity. PTEN phosphatase activity regulated metastasis through Entpd5. Entpd5 knockdown reduced metastasis and IGF1R levels while promoting ER stress. In contrast, Entpd5 overexpression promoted metastasis and enhanced IGF1R levels, while reducing ER stress. Moreover, Entpd5 expression was regulated by the ER stress sensor ATF6. Altogether, our data show that PTEN phosphatase activity inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6, thereby identifying novel candidate therapeutic targets for the treatmtreatingwith PTEN mutant melanoma.

2023-03-09 | GSE210359 | GEO

Emilin1 degradation and secretion in exosomes inactivate its tumor- and metastasis-suppressive role in melanoma mouse models

Project description:Several studies have demonstrated that melanoma-derived exosomes home in sentinel lymph nodes favoring metastasis. Here, we determined the proteomic signature in exosomes derived from lymph node metastatic models. We found a signature of genes over-expressed and proteins hyper-secreted in exosomes related to lymph node metastasis in the B16 mouse melanoma model. Out of these candidates, we found that Emilin1, a protein with an important function in lymph node physiology, was hyper-secreted in exosomes. Interestingly, we found that Emilin1 is degraded and secreted in exosomes as a mechanism favoring metastasis. Indeed, we found that Emilin1 has a tumor suppressor-like role regulating negatively cell viability and migration. Importantly, our in vivo studies demonstrate that Emilin1 overexpression reduced primary tumor growth and metastasis in mouse melanoma models. Analysis in human melanoma samples showed that cells expressing high levels of EMILIN1 are reduced in metastatic lesions. Overall, our analysis suggests a novel mechanism involved in the inactivation of Emilin1 in melanoma favouring melanoma progression and metastasis.

2021-07-16 | PXD018891 | Pride

Discovery of TBC1D7 as a potential driver for melanoma cell invasion.

Project description:Melanoma is a common type of cancer, and metastasis remains the leading cause for mortality in melanoma patients. In this study, we utilized an unbiased mass spectrometry-based quantitative proteomic method to assess, at the global proteome scale, differential protein expression in a matched pair of primary/metastatic melanoma cell lines derived from the same patient, i.e. WM-115/WM-266-4. We found that TBC1D7 is overexpressed in metastatic (WM-266-4) relative to primary (WM-115) melanoma cells. We also observed that elevated expression of TBC1D7 promotes melanoma metastasis in vitro. Bioinformatic analyses of The Cancer Genome Atlas (TCGA) data suggested that higher mRNA expression levels of TBC1D7 predict poorer survival in melanoma patients. Furthermore, we showed that TBC1D7 promotes invasion of cultured melanoma cells in vitro, at least in part, through modulating the expression levels and activities of matrix metalloproteinases 2 and 9 (MMP2 and MMP9). Together, the results from the present study support TBC1D7 as a potential driver for melanoma metastasis.

2022-08-15 | PXD014368 | Pride

Transcription profiling of human melanoma to identify a a gene Signature for aggression of Melanoma Metastases (LeiFidler)

Project description:Metastasis is the deadliest phase of cancer progression. Experimental models using immunodeficient mice have been used to gain insights into the mechanisms of metastasis. We report here the identification of a âmetastasis aggressiveness gene expression signatureâ derived using human melanoma cells selected based on their metastatic potentials in a xenotransplant metastasis model. Comparison with expression data from human melanoma patients shows that this metastasis gene signature correlates with the aggressiveness of melanoma metastases in human patients. Many genes encoding secreted and membrane proteins are included in the signature, suggesting the importance of tumor-microenvironment interactions during metastasis. Experiment Overall Design: parental cell line vs xenograft model

2008-06-15 | E-GEOD-7956 | biostudies-arrayexpress

Transcription profiling of human melanoma to develop a gene signature for aggression of melanoma metastases based on a xenograft mouse model

2008-06-15 | E-GEOD-7929 | biostudies-arrayexpress

Affymetrix SNP array data for metastatic melanoma specimens

Project description:Comparison between the copy number of differentially methylated sites between lymph node metastasis from melanoma patients with good prognosis and melanoma brain metastasis. All samples are taken from different patients, and were established as cell lines in the John Wayne Cancer Institute. Sixteen metastatic melanomas were run on Affymetrix Genome-Wide Human SNP Array 6.0. Lymph node metastases and brain metastases genetic copy number variations were compared.

2013-09-19 | E-GEOD-44019 | biostudies-arrayexpress

Transcription profiling of human melanoma xenotransplant metastatis model - gene signature for aggression of melanoma metastases

2008-06-16 | E-GEOD-8401 | biostudies-arrayexpress

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