Improving fascin inhibitors to block tumor cell migration and metastasis

Abstract

A B S T R A C TTumor metastasis is the major cause of mortality of cancer patients, being responsible for w90% of all cancer deaths. One of the key steps during tumor metastasis is tumor cell migration which requires actin cytoskeletal reorganization. Among the critical actin cytoskeletal protrusion structures are antenna-like filopodia. Fascin protein is the main actinbundling protein in filopodia. Here we report the development of fascin-specific small-molecules that inhibit the interaction between fascin and actin. These inhibitors block the in vitro actin-binding and actin-bundling activities of fascin, tumor cell migration and tumor metastasis in mouse models. Mechanistically, these inhibitors likely occupy one of the actin-binding sites, reduce the binding of actin filaments, and thus lead to the inhibition of the bundling activity of fascin. At the cellular level, these inhibitors impair actin cytoskeletal reorganization. Our data indicate that target-specific anti-fascin agents will have great potential for treating metastatic tumors.

Quantitative assessment of cell contractility using polarized light microscopy

“…A slow acquisition speed presents an issue since cells may have the time to change their morphology over the course of the multi‐images acquisition, thus shifting the spatial position of the birefringent components between each frame. Notably, the rate of membrane protrusion and the speed at which a cell can migrate can be as high as 10 μm min −1 . Any slight frame‐to‐frame shift can introduce artifacts from the computational step that provides false retardance signals.…”

New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells

“…Migrastatin and its macroketone analogs have been found to efficiently inhibit fascin1, thus decreasing metastatic tumor cell migration, invasion, and further metastasis 1 . However, the complex structure of the macroketone hinders its synthesis, and other anti-fascin1 compounds derived from indazol-furan-carboxamides have been tested 11 . To identify novel molecules targeting fascin1 as potential anti-SAC drugs, we performed an in silico compound library screening and subsequent in vitro and in vivo assays to characterize the anti-fascin1, antimigratory, and anti-invasive potential of the selected compounds.…”

Analysis of Fascin-1 in Relation to Gleason Risk Classification and Nuclear ETS-Related Gene Status of Human Prostate Carcinomas: An Immunohistochemical Study of Clinically Annotated Tumours From the Wales Cancer Bank

“…More recently, a small molecule that inhibits actin bundling by fascin-1 was reported to decrease lung metastasis of syngeneic fascin-1–positive breast tumours in mice 18. Therefore, fascin-1 has emerged as a new prospective therapeutic target 19,20…”