FMN2 Generates a Prometastatic Perinuclear Actin Structure

In order to migrate within a tightly confined 3-D microenvironment, cells can remodel their microenvironment or squeeze through constrictions, the latter of which requires nuclear deformation and can damage the nucleus and DNA through mechanical stress. The role of the actin cytoskeleton in protecting the nucleus is unclear, although cytoskeletal–nuclear connections are essential during cell migration. Skau and colleagues found that formin 2 (FMN2), an actin-nucleating protein that generates unbranched actin filaments, localizes to actin bundles and focal adhesions (FA) in the perinuclear membrane at the dorsal cell surface, representing a previously unknown perinuclear actin/FA system compositionally distinct from other actin/FA systems. The FMN2 perinuclear actin structure moved with the nucleus during cell migration, and FMN2 was required for creating and maintaining the perinuclear actin/FA system. In 2-D culture, FMN2 depletion increased nuclear lobularity and nuclear drift from the center of the cell. In transwell migration assays in a 3-D collagen extracellular matrix, FMN2 depletion reduced the number of migrating cells. FMN2 protected the nuclear envelope from damage and prevented DNA double-strand breaks during cell migration in a confined microenvironment, thereby promoting cell survival during migration. FMN2-mediated protection against DNA damage required its actin polymerization activity and generation of the perinuclear actin/FA system. The finding that FMN2 promotes cell survival during migration suggested that it might promote metastasis. Consistent with this hypothesis, in a mouse model of melanoma, FMN2 depletion resulted in a 91% reduction in lung-surface metastases. Together, these findings elucidate a role for FMN2 in creating a perinuclear actin/FA structure that protects the nucleus during confined cell migration, thereby allowing cell survival and metastasis and suggesting the potential for targeting FMN2 to reduce metastasis.

Skau CT, Fischer RS, Gurel P, Thiam HR, Tubbs A, Baird MA, et al. FMN2 makes perinuclear actin to protect nuclei during confined migration and promote metastasis. Cell 2016;167:1571–85.e18.

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