Transient Nuclear Envelope Rupture During Cell Migration: A Cause of Genomic Instability and a Novel Opportunity for Therapeutic Intervention
Abstract
We have demonstrated that the physical stress associated with confined cancer cell migration can result in transient nuclearenvelope rupture in vitro and in vivo, and that the nuclear deformation and nuclear envelope rupture result in nuclearfragmentation and DNA damage. We were able to further show that ESCRT-III proteins play a critical role in the nuclearenvelope 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 cGAS/STINGpathway and promotes cancer metastasis. Inhibition of the cGAS/STING pathway or preventing nuclear envelope rupture byoverexpression of lamin B2 significantly reduced metastasis in a mouse xenograft model. These findings suggest that targetingthese pathways could be a potential therapeutic approach to prevent or reduce metastasis. In addition, we have uncovered amechanism by which nuclear deformation can result in DNA damage, even without nuclear envelope rupture, which couldfurther promote genomic instability in metastatic cancer cells. Furthermore, we have demonstrated that mechanically inducednuclear envelope rupture associated DNA damage and activation of DNA damage responses are also highly relevant in otherdiseases, such as muscular dystrophy, and that targeting these mechanisms can present novel therapeutic strategies.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2020
- Accession Number
- AD1111713
Entities
People
- Jan Lammerding
Organizations
- Cornell University