Duke University Medical Center
lab The Garcia-Blanco Lab

researchAlternative splicing regulation during epithelial-mesenchymal transitions in cancer.
In the great majority of human transcripts protein coding information is found in short exons that are identified and ligated together in the process known as pre-messenger RNA splicing. The complex nature of genes provides for versatility of expression because one gene can encode for many proteins by altering the selection of exons to be included in the messenger. This process is known as alternative splicing and it is the major engine of proteome diversity in humans.


My laboratory studies the regulation of processing of messenger RNAs focusing on the alternative splicing of the fibroblast growth factor receptor-2 (FGFR2) transcripts. FGFR2 transcripts are alternatively spliced to yield regulated expression of two receptors with dramatically different ligand specificity. Not only is this process critical for normal development of many epithelial tissues, but also during progression of prostate tumors the alternative splicing of FGFR2 was noted to be deregulated. The laboratory has pioneered the use of reporter constructs to image alternative splicing decisions in vivo, both in normal tissues in transgenic mice and in syngeneic prostate tumors in rats. In the latter system, imaging of alternative splicing has led to the unexpected discovery of epithelial plasticity (epithelial-mesenchymal and mesenchymal-epithelial transitions) in tumors presumed to be anaplastic. These transitions appear to be essential for tumor progression and the development of metastases, the major cause of morbidty and mortality in cancer patients. This has led to a reevaluation of the importance of a plasticity phenotype in tumor fitness. A major focus of the laboratory is the determination of the signaling pathways that mediate alternative splicing changes during epithelial-mesenchymal transitions in cancer. Furthermore, this work in animal model systems has inspired a collaborative effort with Dr. Andrew Armstrong (a medical oncologist at the Duke Prostate Center) to detect plasticity in human prostate tumors and in circulating cancer cells.