Epithelial plasticity, the ability of cells to transition between epithelial and mesenchymal states, is required for epithelial cancers, including prostate cancer (PC), to metastasize. One of the many changes that occur in response to epithelial plasticity is the alternative pre-mRNA splicing (AS) of cellular transcripts. AS is a major regulatr of mammalian gene expression, and is also involved in cancer cell proliferation, apoptosis and invasiveness. Therefore, it is likely that prostate tumor progression correlates with, or may even be caused by, changes in the regulation of AS. The goal of this research is to characterize the role of epithelial-specific splicing in epithelial plasticity and prostate tumorigenesis using fluorescent AS reporters [in vitro and in vivo in whole animal models, and to validate these findings in human PC patient samples]. Because the microenvironments that are unique to a cell or tissue can alter the AS of transcripts, the use of fluorescent AS reporters allows for the n situ visualization of mRNA splicing decisions made by individual cells. In the proposed experiments, AS factors and a transcription factor that are associated with epithelial plasticity will be expressed in epithelial cells that have been artificially induced to undergo EMT and become mesenchymal. The ability of these cells to alternatively splice the fluorescent mRNA reporters in response to changes in epithelial plasticity will be visualized in cell culture and ina whole animal model of prostate tumor progression. [Human PC samples will also be interrogated for the expression of AS factors, and a transcription factor, that are involved in epithelial plasticity. Ultimately, I will validate the findings from the in vitro and in vivo experiments in human patient samples,] and will validate the biological significance between AS, epithelial plasticity, and human prostate tumorigenesis.

Public Health Relevance

Careful study of the regulation of gene expression in a mouse cancer model may advance our understanding of how gene expression is altered during tumorigenesis and metastasis. This investigation may identify novel biomarkers and therapeutic targets important for the early detection and treatment of prostate cancer, respectively.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32CA165482-01A1
Application #
8398272
Study Section
Special Emphasis Panel (ZRG1-F09-P (20))
Program Officer
Jakowlew, Sonia B
Project Start
2012-11-01
Project End
2013-09-29
Budget Start
2012-11-01
Budget End
2013-09-29
Support Year
1
Fiscal Year
2012
Total Cost
$45,588
Indirect Cost
Name
Duke University
Department
Genetics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Somarelli, J A; Schaeffer, D; Marengo, M S et al. (2016) Distinct routes to metastasis: plasticity-dependent and plasticity-independent pathways. Oncogene 35:4302-11
Schaeffer, Daneen; Somarelli, Jason A; Hanna, Gabi et al. (2014) Cellular migration and invasion uncoupled: increased migration is not an inexorable consequence of epithelial-to-mesenchymal transition. Mol Cell Biol 34:3486-99