Nuclear Envelope Disruptions Induce DNA Damage and Invasiveness

The availability of space is a major limitation proliferating cancer cells encounter, and cell crowding can lead to deformation of the nucleus, rupture of the nuclear envelope (NE), and DNA damage. Mutations that cause this phenomenon have been associated with diseases such as muscular dystrophy, but the role that mechanically induced NE ruptures play in cancer remains to be fully elucidated. Nader and colleagues investigated the extent of nuclear deformation and DNA damage in microinvasive breast ductal adenocarcinoma in situ (DCIS) and observed a marked increase in NE disruption and DNA damage—including in human cancer biopsies—occurring mainly at the tumor periphery and in the presence of cellular confinement. After NE rupture events, the endoplasmic reticulum (ER) exonuclease TREX1, along with other ER-bound proteins, relocalized from the ER to the inner side of the nuclear membrane, which was abrogated when TREX1 was without its C-terminal ER-binding site. The DNA damage induced by TREX1 triggered a senescence phenotype in nontransformed cell lines but not in transformed DCIS cells. Loss of expression of TREX1 reduced DNA damage after NE disruption, and TREX1-depleted cells exhibited the ability to grow at a high density without stimulation of DNA damage but had a reduced ability to migrate and degrade collagen. Analysis of the expression of common EMT-related genes, including SNAIL1, showed an upregulation when cells were in a confined space but was not observed in TREX1-knockout cells, supporting the idea that the ability of cells to invade and degrade matrix may in part be influenced by NE disruption and DNA damage exposure. Murine xenograft studies using these same TREX1-knockout DCIS cells showed significantly reduced invasive tumor formation as well as a diminution of DNA damage at the tumor edge. In summary, this study demonstrates the importance of NE disruption and its subsequent induction of DNA damage on the promotion of an invasive phenotype, particularly in crowded tissues where cells are prone to mechanical stress.

Nader GPF, Agüera-Gonzalez S, Routet F, Gratia M, Maurin M, Cancila V, et al. Compromised nuclear envelope integrity drives TREX1-dependent DNA damage and tumor cell invasion. Cell 2021 Sep 15 [Epub ahead of print].

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