Genomic Variation in an Osteosarcoma Cell Line Caused by Pore Migration

Abstract

Normal and diseased cells in vivo sometimes squeeze their nucleus through tissues and basement membrane matrices. Recent studies has shown that constricted migration give rise to an increase in GFP-53BP1 marked DNA damage and to die more frequently, but any effect on genome integrity is unknown. Similar studies here with one of the cancer cell lines, U2OS osteosarcoma cells, show that such migration increases gH2AX foci, increases electrophoretic displacements of DNA from isolated nuclei, and changes chromosome copy numbers. DNA breaks decrease over time and the cells proliferate normally on rigid plastic, but lasting changes in chromosome copy number are revealed by standard DNA array methods. DNA repair factors tend to be more cytoplasmic after migration, which is consistent with reports of migration-induced nuclear envelope rupture as is cell death due to inhibition of repair. Accumulation of mutations in cancer progression is often associated with the replication stress during cell division. The repair of migration-induced DSBs through the mutation prone non-homologous end joining, could potentially provide an alternative path toward mutation accumulation, increasing intra- and inter-tumor heterogeneity. Genomic instability is closely related to the development and progress of cancer, which is a major disease in the US and around the world. New cures to cancer will benefit from new insights into basic mechanisms of nuclear processes in migration.