The Mena Protein Isoforms

The Mena protein is a key potentiator and modulator of cellular migration and is a prometastatic factor. Mena is involved in the nucleation and polymerization of actin, being a cellular regulator of assembling and dynamic of cytoplasmic actin networks.  It belongs to the Ena/VASP (enabled/VASP) family, along with VASP and Ena-VASP-like, being encoded by Mena gene located on chromosome 1.

Mena is found in the developing embryo where it is an important actor in the developing nervous system among other functions. It facilitates and organizes formation, extension and navigation of growing nerve fibers through tissue to link with other neurons, forming the proper circuits needed for a functional nervous system. Its expression decreases from embryonic to adult life. Studies have revealed that Ena/VASP proteins are involved in those processes where dynamic actin reorganization is necessary, such as neural closure, phagocytosis, hemostasis, chemotaxis, cell migration, cell-cell and cell-matrix adhesions, fibrillogenesis, or fibroblastic motility.

However in metastatic cancer cells, high levels of the Mena protein accumulate and influence a number of intracellular (inside the cell) signaling pathways. Mena facilitates a dangerous process whereby tumor cells send out a well-organized protuberance that invades surrounding tissue and pulls the remainder of the cell behind it. Mena modulates the strength and direction of this invasive process. Mena steers the migrating cancer cell in the direction of blood vessels through its ability to modulate the metastatic cell’s response to chemical signals that attract it to blood vessels.

Mena is present in cancer cells in more than one form. These different varieties, called isoforms, are similar but slightly different in structure. Protein isoforms, despite their similarity in structure, can sometimes have very large differences in their influence on cells. We have identified the most dangerous isoform of Mena,  named MenaINV (Mena invasive). Mena11A, on the other hand, is the Mena isoform that seems to exert a much more positive influence on the cell’s behavior, reducing the ability of cells to break away from the tumor and invade and migrate toward blood vessels.

Our driver-based Mena isoform protein diagnostic biomarkers also serve as novel therapeutic targets for anti-metastatic drugs. Our breakthrough was the discovery of a novel approach through a proprietary mechanism of action to make intracellular Mena isoform proteins drugable targets.