Journal
CURRENT BIOLOGY
Volume 31, Issue 4, Pages 753-+Publisher
CELL PRESS
DOI: 10.1016/j.cub.2020.11.037
Keywords
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Funding
- National Institutes of Health [R01 HL082792, R01 GM137605, U54 CA210184, U54 CA193461]
- National Institutes of Health (NIBIB) [P41-EB002025]
- National Institutes of Health (NSF/NIGMS) [1361375]
- National Institutes of Health (New Innovator) [DP2 GM229133]
- National Institutes of Health (NCI) [U54 CS21018]
- Department of Defense Breast Cancer Research Program (Breakthrough Award) [BC150580]
- National Science Foundation (CAREER Award) [CBET-1254846, 1752226]
- NSF Graduate Research Fellowship [DGE-1650116, DGE-1650441]
- Caroline H. and Thomas Royster Fellowship (UNC, Chapel Hill)
- Volkswagen Foundation
- Gordon and Betty Moore Foundation
- Howard Hughes Medical Institute
- NSF [NNCI-2025233, 1428922]
- New York Stem Cell Foundation (NYSTEM) [CO29155]
- NIH [S10OD018516]
- Direct For Mathematical & Physical Scien
- Division Of Mathematical Sciences [1361375] Funding Source: National Science Foundation
- Directorate For Engineering
- Div Of Civil, Mechanical, & Manufact Inn [1752226] Funding Source: National Science Foundation
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During cancer metastasis, cancer cells migrate through narrow spaces, leading to nuclear deformation, nuclear envelope rupture, and DNA damage. This damage, associated with replication stress, increases genomic instability and could contribute to tumorigenesis.
Cancer metastasis, i.e., the spreading of tumor cells from the primary tumor to distant organs, is responsible for the vast majority of cancer deaths. In the process, cancer cells migrate through narrow interstitial spaces substantially smaller in cross-section than the cell. During such confined migration, cancer cells experience extensive nuclear deformation, nuclear envelope rupture, and DNA damage. The molecular mechanisms responsible for the confined migration-induced DNA damage remain incompletely understood. Although in some cell lines, DNA damage is closely associated with nuclear envelope rupture, we show that, in others, mechanical deformation of the nucleus is sufficient to cause DNA damage, even in the absence of nuclear envelope rupture. This deformation-induced DNA damage, unlike nuclear-envelope-rupture-induced DNA damage, occurs primarily in S/G2 phase of the cell cycle and is associated with replication forks. Nuclear deformation, resulting from either confined migration or external cell compression, increases replication stress, possibly by increasing replication fork stalling, providing a molecular mechanism for the deformation-induced DNA damage. Thus, we have uncovered a new mechanism for mechanically induced DNA damage, linking mechanical deformation of the nucleus to DNA replication stress. This mechanically induced DNA damage could not only increase genomic instability in metastasizing cancer cells but could also cause DNA damage in non-migrating cells and tissues that experience mechanical compression during development, thereby contributing to tumorigenesis and DNA damage response activation.
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