Transient Nuclear Envelope Rupture during Cell Migration: A Cause of Genomic Instability and a Novel Opportunity for Therapeutic Intervention
Technical Report,15 Feb 2018,14 Feb 2019
CORNELL UNIV ITHACA NY ITHACA United States
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We have demonstrated that the physical stress associated with confined cancer cell migration can result in transient nuclear envelope rupture in vitro and in vivo, and that the nuclear deformation and nuclear envelope rupture result in nuclear fragmentation and DNA damage. We were able to further show that ESCRT-III proteins play a critical role in the nuclear envelope repair, and that depleting or inhibiting ESCRT-III and associated proteins delays nuclear envelope repair. In addition, we showed that exposure of genomic DNA to the cytoplasm following nuclear envelope rupture activates the cGASSTING pathway and promotes cancer metastasis. Inhibition of the cGASSTING pathway or preventing nuclear envelope rupture by overexpression of lamin B2 significantly reduced metastasis in a mouse xenograft model. These findings suggest that targeting these pathways could be a potential therapeutic approach to prevent or reduce metastasis. During the current project period, our work on this project has so far resulted in 7 peer-reviewed publications plus one currently in revision, as well as 13seminar, conference or poster presentations by the PI or studentspostdocs from the PIs laboratory. All tasks have been completed according to or ahead of the schedule listed in the original SOW.
- Medicine and Medical Research