Discovery of 'Molecular Switch' May Prevent Metastases

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Researchers have discovered a "switch" called the epithelial splicing regulatory protein, which was found to hold the potential to prevent the metastasis of primary tumors to other organs.

University of Pennsylvania (UPenn) researchers have discovered a “switch” called the epithelial splicing regulatory protein (ESRP), which was found to hold the potential to prevent the metastasis of primary tumors to other organs.

When ESRP is in the “on” position, it maintains the traditional disposition of cells that lie on the surface of organs and body cavities. Epithelial cells are the types from which most solid tumors arise, according to the UPenn release. When the ESRP switch is “off,” the epithelial cells become more mesenchymal cells, and are able to migrate from the primary tumor.

The protein exists in two similar forms, ESRP1 and ESRP2, which—following a high-throughput genetic screening for rare proteins to uncover them—were found to alter how RNAs are spliced together, and can also produce more than one mRNA from the same gene. The mRNA for Fibroblast Growth Factor Receptor 2 (FGFR2) has two forms, including IIIb, which is expressed in epithelial cells, and IIIc, which is expressed in mesenchymal cells.

According to the UPenn release, the IIIb protein interacts with other factors that promote epithelial cell behavior, which is to remain stationary.

When the IIIc form is atypically produced in cancer cells derived from epithelial cells, also according to the UPenn release, the resulting FGFR2 protein type no longer promotes the epithelial cell identity, and switches to the mesenchymal cell type, which can detach from its primary site, invade local tissue, and metastasize to distant sites of the body.

“If we can find a way to maintain expression of ESRP1 and 2 in epithelial cells, then it might be possible to prevent metastasis or control fibrosis,” said Russ P. Carstens, MD, Assistant Professor of Medicine and one author of the study. “ESRP1 and ESRP2 are necessary for splicing FGFR2 mRNA in the epithelial cell manner. This is one of few known splicing factors that operate in a clear-cut, cell-type-specific manner. Epithelial cells, which make up the lining of organs, are the only cells that produce ESRP1 and ESRP2.”

To read an abstract of the study that appeared in the journal Molecular Cell, click here.

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