Posted: June 18, 2013

Analysis Using TCGA Data Identifies New Therapeutic Possibility

Emma J. Spaulding

Research conducted by Wei Zhang, Ph.D. and his colleagues describing a method to prevent the spread of ovarian cancer in both in-vitro and in-vivo models was published in the Feb. 11, 2013 issue of Cancer Cell. Ovarian cancer develops in the tissues of one or both ovaries, which are situated in the abdominal cavity and buffered by peritoneal fluid. If ovarian cancer spreads through the abdominal cavity via this fluid, the disease becomes more difficult to treat and surgery to remove the cancerous tissue is often inadequate. Roughly 30 percent of patients survive for five years following diagnosis with an advanced stage of ovarian cancer. There would be great therapeutic potential if the spread of ovarian cancer via the peritoneal fluid could be prevented.

In an effort to better understand ovarian cancer invasion, Dr. Zhang and his colleagues analyzed the multidimensional data of 459 serous ovarian cancer cases characterized by The Cancer Genome Atlas (TCGA), as well as 560 more cases from independent cohorts. The scientists hypothesized that analyzing miRNAs (small non-coding pieces of RNA), in association with genomic, epigenetic, and mRNA expression data, would allow them to identify the molecular driver events of the mesenchymal subtype, which was described in TCGA’s 2011 publication, Integrated genomic analyses of ovarian carcinoma.

MiRNAs stop expression of proteins, either by preventing them from being translated or degrading the mRNA, a precursor to the protein. When analyzing the integrated genomic data, the scientists found indications that the mesenchymal subtype was likely governed by a miRNA regulatory network. In particular, eight miRNAs were predicted to moderate 89 percent of miRNA associated genes. Among the eight miRNAs, miR-506 exhibited the most significant downregulation in the subtype and was found to perform several key cellular functions that may contribute to metastasis of the ovarian cancer.

This metastasis is thought to be sometimes caused by deviation from a normal process that occurs in embryo development when some of the epithelial cells assume mesenchymal characteristics. Epithelial cells are a component of the lining covering the organs in the body cavity. One of their most important functions is to promote cellular adhesion, or how cells bind to one another, ensuring the epithelial membrane doesn’t have gaps. In contrast, mesenchymal cells have loose cellular adhesion.

In embryogenesis, these epithelial-turned-mesenchymal cells show decreased cellular binding and therefore, increased motility and promotion of migration to their target organs, a process called epithelial-to-mesenchymal transition (EMT). In cancer however, ovarian epithelial cells may aberrantly undergo the same transition, where they promote the same migration, causing metastasis in the abdominal cavity. In this study as well as in others1,2, EMT was associated with poor patient outcomes.

To further understand miR-506 and its role in ovarian cancer metastasis, the scientists performed functional experiments in cell lines. The cell lines were transfected with either miR-506 or a scrambled miRNA, which served as a control. The cells that expressed miR-506 developed an epithelial signature that showed induction of E-cadherin, a protein involved in cell-to-cell adhesion as well as suppression of the mesenchymal markers. The research showed that increased levels of miR-506 correlated with increased expression of E-cadherin. Decreased expression, or loss of E-cadherin, correlated with a decrease in cellular adhesion. This is a potential cause of metastasis in the abdominal cavity.

The scientists reasoned that if they could increase levels of miR-506, E-cadherin expression would increase as well. Thus, EMT would be less likely to occur, as would the cancer’s invasion into other organs. To explore the potential of delivering miR-506 in-vivo, the scientists designed two mouse models using ovarian cancer cell lines. They delivered miR-506 to the mouse models by nanoparticles, an emerging technology in which very small particles loaded with the drug of interest are introduced into the animal model’s peritoneal fluid. Nanoliposomes, bilayer lipid vesicles, were used as the vector for the nanoparticle delivery of miR-506. For both mouse models, delivery of miR-506 significantly reduced the number of tumor nodules and the overall tumor weight.

This research presents a therapeutic opportunity to utilize a nanoparticle delivery system for treatment. Several nanoparticle cancer drugs have been clinically approved, and many more are in development. In sum, the scientists concluded that nanoparticle delivery of miR-506 lead to E-cadherin induction, preventing cells from invading other organs and hence, reducing tumor growth in the mouse models. These results were supported by the cell line transfection experiment in this study. This research by Dr. Zhang and his colleagues leverages new technology to develop novel treatment options to prevent ovarian cancer from undergoing EMT. With additional research, these findings could help improve patient outcomes.

Because the scientists could access TCGA’s integrated and multidimensional ovarian cancer data, they were able to draw the important conclusion that miR-506 was an important driver of ovarian cancer. Dr. Zhang and his colleagues used this information to develop a method for delivering miR-506 as a therapy to in-vitro and in-vivo models, demonstrating the exciting research which can be built upon TCGA data.

Yang, D., Sun, Y., Hu, L., Zheng, H., Ji, P., Pecot, C.V., Zhao, Y., Reynolds, S., Cheng, H., Rupaimoole, R., et al. (2013) Integrated analyses identify a master microRNA regulatory network for the mesenchymal subtype in serous ovarian cancer. Cancer Cell. 23(2):186-199. View PubMed abstract

Selected References

Davidson, B., Tropé, C.G., and Reich, R. (2012) Epithelial–mesenchymal transition in ovarian carcinoma. Front Oncol. 2012;2:33. Read the full article

2 Shirkoohi, R. (2013) Epithelial mesenchymal transition from a natural gestational orchestration to a bizarre cancer disturbance. Cancer Sci. 2013 Jan;104(1):28-35. Read the full article