Molecular Mechanisms of Fascin in Cancer Progression

Invasion and metastasis represent the primary sources of morbidity and mortality in most cancers. Defining and validating therapeutic targets to eliminate these malignant mechanisms remains of critical importance in cancer biology. Fascin is an actin crosslinking protein that organizes F-actin into tightly packed bundles. Consequently, it is typically localized to actin-based structures such as filopodia. In humans, Fascin is normally expressed throughout development of the nervous system, and in adult vascular endothelial cells and mesenchymal cells. However, Fascin is frequently aberrantly expressed in human cancers of epithelial origin, where it is normally not expressed. Though Fascin expression is correlated with invasion, metastasis, and poor prognosis in many cancers, the mechanism underlying its contribution to cancer progression is not well defined and requires further investigation. Here, we uncovered an oncogenic mechanism of Fascin that may explain its effects on tumor growth, invasion and metastasis. We show that cells that express Fascin are able to generate long and thin cell-cell connections called tunneling nanotubes, and we provide evidence that tunneling nanotubes may be a simple result from changes in cell-cell adhesions. Fascin expression causes defects in cell-cell adhesions in both 2D monolayer and 3D tumor sphere cultures. These defects coincided with localization of β-catenin away from cell-cell adhesions, and into nuclei. Additionally, we show that Fascin promotes activation of the developmental and stem cell Wnt/β-catenin signaling pathway, and expression of proliferation, transformation, and invasion genes. Pharmacologic inhibition of Fascin disrupts the interaction between Fascin and β- catenin, and is able to block 3D invasion of tumor cells by preventing Wnt/β-catenin signaling at the tumor edge. Colorectal cancers have shown to be particularly addicted to oncogenic Wnt/β-catenin signaling, but drugs targeting the pathway have not reached the clinic, possibly due to the pathway’s fundamental importance in maintenance of adult stem cells. Through these studies, we provide evidence that pharmacologic inhibition of Fascin may be a promising strategy to mitigate oncogenic Wnt/β-catenin signaling to prevent malignant progression of cancers.