(702c) Perinuclear Actin Flow Promotes Efficient Cell Migration in Confinement

Cell migration is a fundamental cellular phenomenon that plays pivotal role during cancer metastasis. Although our current understanding of tumor cell migration stems primarily from studies using 2D substrates or 3D collagen gels, advances in intravital microscopy suggest that in vivo cells migrate preferably along 3D preexisting longitudinal channels/tracks which impose varying degrees of confinement on cells. In confined microenvironments, the nucleus, which is the stiffest cellular compartment, has a rate-limiting role and reduces the efficiency of cell locomotion. To overcome this barrier, tumor cells develop a mechanism which facilitates nuclear deformation and translocation. Using bioengineering tools (microfluidics), high-resolution imaging and mathematical modeling based on lubrication theory, we have discovered that confinement induces the formation of perinuclear actin flow which increases the gap and reduces the friction generated between the nucleus and the channel wall, thereby promoting efficient migration. We also delineated the molecular mechanisms responsible for regulating perinuclear actin flow by studying the role of small GTPases, actin nucleators and the LINC complex. Collectively, our work identifies a novel regulator of tumor cell motility and enhances our understanding of the complex process of confined cell migration.