Accession Number:

AD1111713

Title:

Transient Nuclear Envelope Rupture During Cell Migration: A Cause of Genomic Instability and a Novel Opportunity for Therapeutic Intervention

Descriptive Note:

Technical Report,15 Feb 2016,14 Feb 2020

Corporate Author:

CORNELL UNIVERSITY ITHACA United States

Personal Author(s):

Report Date:

2020-06-01

Pagination or Media Count:

382.0

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 cGASSTINGpathway and promotes cancer metastasis. Inhibition of the cGASSTING 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.

Subject Categories:

  • Medicine and Medical Research
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE