The mechanical stress exerted on a cell that translocates through confined 3D microenvironments can damage the nucleus and DNA. Waterman and colleagues report that FMN2, a member of the formin family of actin nucleators, mediates the formation of a perinuclear actin structure that protects the cell from nuclear damage during confined migration, thereby aiding cancer metastasis (Cell 167, 1571–1585; 2016).

The authors demonstrated that FMN2 was necessary for the formation of a system of perinuclear actin and focal adhesions at the dorsal surface of cultured cells, which supported nuclear positioning during 2D migration. A similar FMN2–actin network was observed in 3D collagen cell cultures. FMN2 depletion reduced the survival of cells migrating in this 3D system, which was associated with nuclear envelope rupture and DNA double-strand breaks. This nucleus-protective role of FMN2 required its actin-nucleating activity. Exploring the role of FMN2 in a cancer setting, the authors showed that FMN2 mediated the formation of a perinuclear actin network in melanoma cells, and supported their survival during confined invasion in vitro. In vivo, FNM2 deficiency decreased melanoma metastasis, and increased the number of cells with DNA damage, whereas its overexpression had the opposite effect.

Thus, the FMN2-generated perinuclear actin cage that protects the nucleus from mechanically induced damage may be deregulated in cancer to enhance metastasis.