TY - JOUR
T1 - Nuclear plasticity increases susceptibility to damage during confined migration
AU - Mukherjee, Abhishek
AU - Barai, Amlan
AU - Singh, Ramesh K.
AU - Yan, Wenyi
AU - Sen, Shamik
PY - 2020/10/9
Y1 - 2020/10/9
N2 - Large nuclear deformations during migration through confined spaces have been associated with nuclear membrane rupture and DNA damage. However, the stresses associated with nuclear damage remain unclear. Here, using a quasi-static plane strain finite element model, we map evolution of nuclear shape and stresses during confined migration of a cell through a deformable matrix. Plastic deformation of the nucleus observed for a cell with stiff nucleus transiting through a stiffer matrix lowered nuclear stresses, but also led to kinking of the nuclear membrane. In line with model predictions, transwell migration experiments with fibrosarcoma cells showed that while nuclear softening increased invasiveness, nuclear stiffening led to plastic deformation and higher levels of DNA damage. In addition to highlighting the advantage of nuclear softening during confined migration, our results suggest that plastic deformations of the nucleus during transit through stiff tissues may lead to bending-induced nuclear membrane disruption and subsequent DNA damage.
AB - Large nuclear deformations during migration through confined spaces have been associated with nuclear membrane rupture and DNA damage. However, the stresses associated with nuclear damage remain unclear. Here, using a quasi-static plane strain finite element model, we map evolution of nuclear shape and stresses during confined migration of a cell through a deformable matrix. Plastic deformation of the nucleus observed for a cell with stiff nucleus transiting through a stiffer matrix lowered nuclear stresses, but also led to kinking of the nuclear membrane. In line with model predictions, transwell migration experiments with fibrosarcoma cells showed that while nuclear softening increased invasiveness, nuclear stiffening led to plastic deformation and higher levels of DNA damage. In addition to highlighting the advantage of nuclear softening during confined migration, our results suggest that plastic deformations of the nucleus during transit through stiff tissues may lead to bending-induced nuclear membrane disruption and subsequent DNA damage.
UR - http://www.scopus.com/inward/record.url?scp=85094198465&partnerID=8YFLogxK
U2 - 10.1371/journal.pcbi.1008300
DO - 10.1371/journal.pcbi.1008300
M3 - Article
C2 - 33035221
AN - SCOPUS:85094198465
VL - 16
JO - PLoS Computational Biology
JF - PLoS Computational Biology
SN - 1553-7358
IS - 10
M1 - e1008300
ER -