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Updated: Apr 26, 2026
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
Identification and validation of genes with expression patterns inverse to multiple metastasis suppressor genes in
Natascia Marino1, Joshua W Collins, Changyu Shen
1Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Building 37/Room 1126, 37 Convent Drive, Bethesda, MD, 20892, USA, natasciam28@gmail.com.
Abstract:
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. Genes have been identified with expression patterns inverse to a single MSG, and found to encode functional, druggable signaling pathways. We now hypothesize that common signaling pathways mediate the effects of multiple 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. Five genes were selected for further analysis: PDE5A, UGT1A, IL11RA, DNM3 and OAS1. After stable downregulation of each candidate gene in the aggressive human breast cancer cell line MDA-MB-231T, in vitro motility was significantly inhibited. Two stable clones downregulating PDE5A (phosphodiesterase 5A), an enzyme involved in the regulation of cGMP-specific signaling, exhibited no difference in cell proliferation, but reduced motility by 47 and 66 % compared to the empty vector-expressing cells (p = 0.01 and p = 0.005). In an experimental metastasis assay, two shPDE5A-MDA-MB-231T clones produced 47-62 % fewer lung metastases than shRNA-scramble expressing cells (p = 0.045 and p = 0.009 respectively). This study demonstrates that previously unrecognized genes are inversely related to the expression of multiple MSGs, contribute to aspects of metastasis, and may stand as novel therapeutic targets.
Insights
Metastasis suppressor genes (MSGs) control cancer spread. Researchers found new genes inversely related to MSGs that inhibit cancer metastasis, offering potential new therapeutic targets for blocking cancer spread.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Metastasis suppressor genes (MSGs) are crucial for understanding and inhibiting cancer spread.
- Identifying novel genes inversely correlated with MSGs can reveal new therapeutic targets for metastasis.
- Previous research identified genes with expression patterns opposite to single MSGs.
Purpose of the Study:
- To identify novel genes inversely correlated with multiple MSGs.
- To investigate the role of these candidate genes in cancer cell motility and metastasis.
- To evaluate potential therapeutic targets for inhibiting cancer metastasis.
Main Methods:
- Gene expression profiling of MCF7 breast carcinoma cells with siRNA-mediated knockdown of 19 MSGs.
- Identification of genes with expression patterns inversely correlated to at least five MSGs.
- Functional analysis of candidate genes (PDE5A, UGT1A, IL11RA, DNM3, OAS1) in MDA-MB-231T cells, including in vitro motility and experimental metastasis assays.
Main Results:
- Five candidate genes were identified, including PDE5A.
- Downregulation of candidate genes significantly inhibited in vitro cell motility.
- Knockdown of PDE5A (phosphodiesterase 5A) in MDA-MB-231T cells reduced motility by 47-66% and lung metastases by 47-62% without affecting proliferation.
Conclusions:
- Previously unrecognized genes are inversely related to multiple MSGs.
- These genes play a role in cancer cell motility and metastasis.
- Targeting genes like PDE5A represents a novel therapeutic strategy for inhibiting cancer metastasis.
