Abstract 2875: Genes associated with neuronal development, including splicing regulatory factors, increase in expression across epithelial-mesenchymal transition

The program by which epithelial cells lose their polarity and close contacts with neighboring cells and acquire migratory and invasive properties is known as epithelial-mesenchymal transition (EMT). Initially identified as a critical developmental process, EMT is now understood to occur during cancer, where it has been shown to confer resistance to senescence and apoptosis. Previous work indicates that cancer cells that escape the site of the primary tumor hijack at least a portion of the EMT program to increase their invasive properties and metastasize. Earlier work in the field has focused on cell signaling and transcriptional regulation changes that lead to EMT, but changes in the gene expression and post-transcriptional regulation of the cell have only recently become the focus of study. We characterized gene expression and splicing across EMT in the luminal epithelial MCF7ras SLUG+SOX9 breast cancer cell line by collecting samples at 2-day intervals across its 6-day transition and profiling the RNA by RNA-seq. We found over 4,000 significantly changing genes, and that the majority of gene expression and splicing changes occurred in the first two days of the transition, with few changes noted between days 4 and 6. Genes that changed could be broadly categorized into those whose expression decreased, increased, or peaked in the middle of the transition before decreasing. Intriguingly, genes whose expression increased during EMT were enriched for gene ontology terms related to cell signaling and neuronal development. We specifically observed increased expression of mRNAs encoding splicing factors and other RNA-binding proteins (RBPs) associated with neuronal development, in contrast to the majority of RBPs whose expression decreases in EMT. We are currently exploring various aspects of this program, including effects of increased expression of the neuronal-associated splicing regulatory factor quaking (QKI). These may include downregulation of the Notch pathway via effects on splicing of NUMB, a Notch inhibitor. We are currently validating the role of QKI on this and other RNA processing changes and will report our findings. Citation Format: Yevgenia L. Khodor, Daisy Riquelme, Frank Gertler, Christopher B. Burge. Genes associated with neuronal development, including splicing regulatory factors, increase in expression across epithelial-mesenchymal transition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2875.