The spread of tumor cells from primary sites often occurs as associated cell collectives. In this form of invasion, the contribution of cells leading the way may differ from those that follow. By implication, proteins that regulate the actin cytoskeleton, a major driver of cell motility, may have different roles depending on whether they are in leading or following cells. The LIM kinases 1 and 2 (LIMK) phosphorylate and inactivate the filamentous actin severing function of cofilin proteins. Using siRNA or pharmacological inhibitors, LIMK was found to be required in leading cells of collectively invading tumor cells, or in cancer-associated stromal fibroblasts, for effective extracellular matrix degradation that facilitates three-dimensional invasion. The decreased extracellular matrix degrading activities were associated with an inability to form the stable filamentous actin structures necessary to make matrix-degrading protrusive structures. However, LIMK was not required for cell motility or for path-following in associated collectives. These findings show that leading and following cells in collective invasion have different properties and indicate that targeting the activities in leading cells is sufficient to significantly inhibit tumor cell invasiveness.
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