Local, transient tensile stress on the nuclear membrane causes membrane rupture

Abstract

Cancer cell migration through narrow constrictions generates compressive stresses on the nucleus that deform it and cause rupture of nuclear membranes. Nuclear membrane rupture allows uncontrolled exchange between nuclear and cytoplasmic contents. Local tensile stresses can also cause nuclear deformations, but whether such deformations are accompanied by nuclear membrane rupture is unknown. Here we used a direct force probe to locally deform the nucleus by applying a transient tensile stress to the nuclear membrane. We found that a transient (∼0.2 s) deformation (∼1% projected area strain) in normal mammary epithelial cells (MCF-10A cells) was sufficient to cause rupture of the nuclear membrane. Nuclear membrane rupture scaled with the magnitude of nuclear deformation and the magnitude of applied tensile stress. Comparison of diffusive fluxes of nuclear probes between wild-type and lamin-depleted MCF-10A cells revealed that lamin A/C, but not lamin B2, protects the nuclear membranes against rupture from tensile stress. Our results suggest that transient nuclear deformations typically caused by local tensile stresses are sufficient to cause nuclear membrane rupture.

Mechanics of nuclear membranes

“…Super-resolution imaging studies have suggested that the size of holes in ruptured nuclear membranes is of the order of 100 nm (Denais et al, 2016). This experimental evidence is supported by estimates of the hole size from measurements of the kinetics of fluorescent probe decay from the nucleus upon rupture (Zhang et al, 2019). These sizes are much larger than hole sizes for single bilayer membranes, which tend to be of the order of a few nanometers.…”

“…Importance of nuclear membrane mechanics in the context of nuclear rupture Single lipid membranes are only able to undergo 2-5% areal stretch, beyond which they rupture (Rawicz et al, 2000). A recent development relevant in the context of nuclear membrane mechanics is that fused nuclear membranes have also been observed to undergo rupture in cells (Denais et al, 2016;Hatch and Hetzer, 2016;Raab et al, 2016;Zhang et al, 2019). Membrane rupture is detrimental to cells as it exposes nuclear contents to the cytoplasm and vice versa, causing DNA damage, which has negative consequences for cell function (Denais et al, 2016;Irianto et al, 2017).…”

Correlating nuclear morphology and external force with combined atomic force microscopy and light sheet imaging separates roles of chromatin and lamin A/C in nuclear mechanics

“…However, here we are primarily concerned with morphology in regards to general nuclear shape. A variety of metrics have been used to quantify changes in nuclear morphology, such as area strain (percent change in projected cross-sectional area) (Zhang et al 2019) and 3D irregularity (ratio of excess volume of a fitted convex hull to nuclear volume) (Tocco et al 2018). Aside from the previously noted connections to disease, nuclear morphology has further been linked to levels of transcriptional activity as nuclei with reduced volume enter a more quiescent state (Damodaran et al 2018).…”

Nuclear Plasticity Increases Susceptibility to Damage During Confined Migration

“…Nuclear membrane rupture in micropipette aspiration experiments has been attributed to tensile stresses at the anterior periphery of the nucleus [59,62]. Similar results have been recapitulated by Cao et al [3] in their model where they proposed that the front edge of the nucleus might be susceptible to tensile-stress induced damage during migration through ECM-like environments.…”