Cancer metastasis is the major contributing factor to the majority of cancer-related deaths. Understanding the regulation and molecular mechanisms contributing to the promotion of cancer metastasis is paramount to developing new preventative measures and treatments. The epithelial-mesenchymal transition (EMT) is a fundamental biological process where epithelial cells transform into fibroblastic mesenchymal cells capable of migrating and invading other tissues. Increasing evidence suggests that cancer cells hijack EMT in order to become metastatic. Much of the current research into the regulation of EMT and cancer metastasis focuses on transcription factors and signaling events, however alternative mRNA splicing is emerging as a major regulatory network that governs EMT and metastatic transitions. This proposal seeks to characterize the key splicing events that mechanistically drive EMT as well as the splicing regulatory components that control alternative splicing of these events in order to gain insight into the regulation of cancer metastasis. One of the most differentially spliced genes during EMT is APLP2, a member of the amyloid precursor protein family, which is expressed in many tissues and is involved in cell migration, adhesion, proliferation, and wound healing. However, the specific function of APLP2, especially its splice isoforms, is unknown. Exon 7 of APLP2 encoding a Kunitz Protease Inhibitor (KPI) domain is alternatively spliced during EMT yielding a long isoform (APLP2-L) and short isoform (APLP2-S). The central hypothesis of this project is that alternative splicing of APLP2 is essential for EMT and breast cancer metastasis. This hypothesis will be addressed through two specific aims that explore the mechanistic contribution of alternative splicing of APLP2 to APLP2 proteolytic processing, EMT, and cancer metastasis as well as the regulation of APLP2 alternative splicing.
Aim 1 seeks to determine if APLP2 alternative splicing is essential for EMT and cancer metastasis and whether APLP2 alternative splicing causally controls switching of APLP2 proteolytic processing from an ?-secretase to a -secretase pathway.
Aim 2 will determine the trans-acting splicing factors and cis-acting elements in APLP2 pre-mRNA that facilitate alternative splicing of APLP2. Together these aims will describe the critical role of alternative splicing in EMT and cancer metastasis as well as offering an exciting new therapeutic approach for the treatment of metastatic breast cancer by targeting the APLP2 splicing pathway.

Public Health Relevance

The majority of cancer-related deaths are caused when cancer cells metastasize from the primary location where the tumor originates to other organs in the body, and this is assisted by the process called epithelial- mesenchymal transition (EMT) enabling cancer cells to migrate and invade adjacent tissues. The goal of this project is to examine how alternative splicing of mRNA regulates EMT and promotes cancer metastasis. To accomplish this goal, I will study the alternative splicing of the gene APLP2 in order to provide insight into how cancer gains the ability to metastasize with the hopes of discovering new ways to treat cancer and prevent metastasis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Damico, Mark W
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Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Harvey, Samuel E; Cheng, Chonghui (2016) Methods for Characterization of Alternative RNA Splicing. Methods Mol Biol 1402:229-241