Reversibility of Nuclear and 3D Genomic Changes in Non-Cancerous Fibroblasts After Constricted Migration

Metastatic cancer cells and healthy fibroblasts must traverse constrictive spaces to reach secondary sites. After passing through multiple constrictions, cancer cells often experience stable changes to their nucleus morphology, 3D genome structure, and migratory phenotype. Here, we investigate whether fibroblasts (BJ-5ta), which are non-cancerous and have an inherent ability to migrate to fulfill roles in wound repair, likewise experience nuclear and 3D genomic changes with constricted migration. We find that BJ-5ta cells do not get progressively better at migrating with sequential attempts but do experience nuclear deformations and 3D genome alterations at the compartment level after constricted migration. Transient compartment shifts spatially rearranged genes associated with preparation for and response to migration. Unlike the stable changes associated with long term phenotype changes in cancer cells, however, the nucleus deformations recovered back to unmigrated levels following proliferation and cell movement. Some compartment changes persist and might influence responses to future stimuli, but most 3D genome changes revert to the unmigrated state after cell proliferation. Our study shows that non-cancerous migratory cells are not more robust against alterations caused by constricted migration but can recover from the ones that do arise more readily than cancer cells. Significance StatementO_LICancer cells experience stable phenotype shifts and 3D genome changes after constricted migration, but it is unknown whether these changes would occur in innately migratory non-cancerous fibroblasts. C_LIO_LIFibroblasts (BJ-5ta) show reversible nuclear morphology and 3D genome alterations after constricted migration. C_LIO_LIOur results reveal the connection between basic nucleus mechanobiology and genome structure in fibroblasts, showing how these cells adapt and respond to the forces of constriction during processes such as wound healing. C_LI