Mechanochemical induction of nuclear condensates during cell confined migration.

Abstract

Cell movement through small constrictions is important in many physiological and disease contexts, such as in cancer metastasis. Such migration is rate-limited by squeezing the cell nucleus through the constriction, with associated deformation of the nuclear lamina and chromatin. However, other subnuclear structures are similarly deformed, including membraneless nuclear bodies or condensates, where the impact of cell mechanics on their formation by liquid-liquid phase separation is largely unknown. Here we investigate the response of chromatin-embedded nuclear condensates under mechanical stress using a microfluidic device. We find that the DNA damage response protein 53BP1 undergoes a switch in phase behavior at the rear of migrating breast cancer cell nucleus, independent of DNA damage response. Interestingly, confined migration does not induce nuclear condensation of phase-separated prone FET family proteins. We hypothesize that 53BP1 and potentially other nuclear condensates can sense mechanical stimuli by changing their phase behavior, which is thereby closely coupled to the heterogeneity of the chromatin network they are embedded in. By quantitatively mapping the displacement field of chromatin, we found that chromatin forms spatially distinct domains of correlated motions as well as different strain magnitudes. Our finding highlights the mechanical interplay between nuclear condensates and chromatin under physiological deformations, and suggests the potential role of LLPS in mechanochemical transduction.