Investigation of a process called alternative splicing is a primary focus of research in the lab of Russ P. Carstens, MD, associate professor of Medicine in the University of Pennsylvania School of Medicine. In recent studies, his group has implicated this process in key steps of cancer progression.
ESRP proteins regulate epithelial-specific splicing. In epithelial cells binding of ESRP proteins downstream of an exon promotes its splicing, whereas ESRP binding upstream of or within an exon causes exon skipping (left). ESRP expression is turned off during the EMT and the resulting switch in splicing produces protein isoforms that contribute to the cellular changes that result in mesenchymal cells with increased migration (right). Russ P. Carstens, MD, University of Pennsylvania School of Medicine
Most solid tumors arise from epithelial cells that line the surface of organs and body cavities. When these tumor cells maintain their epithelial characteristics, they are less likely to spread to distant sites. Epithelial cells can be induced to undergo a change characterized by an increase in motility through a process called the epithelial to mesenchymal transition (EMT).
Though EMT is a critical process during the development of embryos, it can be aberrantly reactivated in tumors, contributing to cancer metastasis. In cancer, when certain molecular switches are turned off or absent, tumor cells acquire characteristics of mesenchymal cells and gain the ability to migrate away from the primary tumor.
An important master-switch that is turned off during the EMT is called the epithelial splicing regulatory protein (ESRP). Proteins in this family are able to change how pre-messenger RNAs (pre-mRNA) produced from genes are spliced together in different ways so that there can be more than one mRNA derived from a single gene. These mRNAs go on to code for proteins that often demonstrate opposing functions.
Carstens and Claude Warzecha, PhD, a postdoc in the Carstens’ lab, recently collaborated with Yi Xing’s group at the University of Iowa and Wei Guo’s lab from the Biology Department at Penn in a study published in The EMBO Journal that identified a network of hundreds of alternative splicing events within genes that act to control cell migration. These splicing changes were all controlled by ESRP proteins, suggesting they are true master regulators required to maintain epithelial cell properties. When the ESRPs are turned off in epithelial cells, the cells change shape, have increased migration, and demonstrate other hallmarks of the EMT. An important implication of this work is the ESRP-regulated “splicing signature,” which represents a biomarker that can be used to classify cancer cell types so may have important diagnostic and prognostic implications for human cancers. What’s more, identification of compounds that can restore ESRP expression may guide the development of future cancer therapies targeted at preventing or slowing metastasis.
