Perinuclear Arp2/3-driven actin polymerization enables nuclear deformation to facilitate cell migration through complex environments

Abstract

Cell migration has two opposite faces: although necessary for physiological processes such as immune responses, it can also have detrimental effects by enabling metastatic cells to invade new organs. In vivo, migration occurs in complex environments and often requires a high cellular deformability, a property limited by the cell nucleus. Here we show that dendritic cells, the sentinels of the immune system, possess a mechanism to pass through micrometric constrictions. This mechanism is based on a rapid Arp2/3-dependent actin nucleation around the nucleus that disrupts the nuclear lamina, the main structure limiting nuclear deformability. The cells' requirement for Arp2/3 to pass through constrictions can be relieved when nuclear stiffness is decreased by suppressing lamin A/C expression. We propose a new role for Arp2/3 in three-dimensional cell migration, allowing fast-moving cells such as leukocytes to rapidly and efficiently migrate through narrow gaps, a process probably important for their function.

Cellular functions of the ADF/cofilin family at a glance

“…There is evidence that deformability of the nuclear envelope is a property of cancer cells that facilitates successful cell migration and invasion through complex 'crowded' environments, and actin mediates this deformability (Davidson et al, 2014;Thiam et al, 2016). This is in keeping with our own data that the activities of ADF and CFL1 in cancer cells are required for maintenance of cell shape, nuclear integrity and cell viability, and loss of ADF and CFL1 causes irreversible nuclear deformation (Kanellos et al, 2015).…”

Nuclei migrate through constricted spaces using microtubule motors and actin networks in C. elegans hypodermal cells

“…This would place TOCA-1 in position to interact through cdc42, WAVE and/or Arp2/3 components to nucleate branched actin networks, which could provide additional shape-altering forces. In support of this model, Thiam et al (2016) showed that actin accumulates at the opening of the constricted space as dendritic cell nuclei migrate through an in vitro constriction. However, we observed no gross defects in the actin network of P cells in unc-84(n369); toca-1(tm2056), toca-1(tm2056);toca-2(RNAi) or wve-1(RNAi) animals, although we observed previously reported P-cell nuclear migration defects Xiong et al, 2011) (data not shown).…”

How cells respond to environmental cues – insights from bio-functionalized substrates

“…These thin actin protrusions differ in nature from the bulky actin protrusions, which are used to crawl across the matrix pores and termed lobopodia, that appear when cells move in a dense 3D matrix (Petrie et al, 2012). The use of a 3D matrix with controlled pore sizes has also enabled the investigation of mechanical nuclear deformation during migration and its consequences for DNA damage (Petrie et al, 2014;Raab et al, 2016;Thiam et al, 2016).…”