Transient Nuclear Envelope Rupture during Cell Migration: A Cause of Genomic Instability and a Novel Opportunity for Therapeutic Intervention
Abstract
Breast cancer is a constantly evolving disease. Successive genetic mutations and alterations, often over a prolonged period of time, cause some breast cancers to grow beyond control, invade surrounding tissues, and disseminate through the body. This spreading to other tissues and organs (known as metastasis) is responsible for virtually all deaths in breast cancer. Importantly, it is well recognized that cancer cells are more prone to further changes in their genetic information than normal cells, a feature known as "genomic instability." Genomic instability can drive cancer metastasis and resistance to therapies; accordingly, increased genomic instability is associated with more negative clinical outcomes such as reduced disease-free survival. Rationale and Objective: The cause for increased genomic instability in cancer cells remains incompletely understood; defects in the repair and maintenance of genetic information, housed in the cell nucleus, are thought to play crucial roles. The central hypothesis of this proposal is that temporary mechanical disruption of the nucleus during cancer cell migration through tight spaces can induce genomic instability in breast cancer and contribute to cancer progression and metastasis. As cancer cells invade surrounding tissues and make their way to distant metastatic sites, the cells, and particularly their nucleus, must undergo severe deformations to squeeze through microscopic spaces between other cells and within dense tissues. Preliminary findings from our laboratory suggest that the mechanical forces acting on the cell nucleus during this passage can result in physical damage to the cell nucleus and the genetic information contained inside. Surprisingly, the vast majority of cancer cells survive such seemingly catastrophic damage and continue their journey by rapidly repairing the break in the nuclear membranes. Nonetheless, our preliminary studies suggest that the transient disruption of the cell nucleus induces genomic instability, which could make the affected cells more resistant to therapies and promote metastasis. We recently developed advanced experimental tools to detect nuclear disruption in living cells and tissues. Applying these techniques to a panel of different breast cancer cells and healthy controls, we will (i) assess the effect of transient nuclear rupture on genomic instability, (ii) investigate whether the susceptibility to nuclear damage correlates with the aggressiveness or metastatic potential of cancer cells, (iii) determine how cells manage to overcome repetitive nuclear disruption and repair their nuclear envelope, and (iv) test if targeting these mechanisms can reduce or prevent breast cancer cell invasion and metastasis in vitro and in vivo. Applicability of the Research: Our studies will help identify why some breast cancers become life-threatening metastases and provide new approaches to distinguish aggressive breast cancer from indolent cancers. This can lead to new therapeutic approaches to reduce the mortality associated with metastatic breast cancer. Our research will reduce the risk of metastatic cancer by aiming to identify key characteristic features of invasive and metastatic cancer cells that could be exploited to specifically target these cells with novel therapies, particularly by interfering with their ability to withstand and repair nuclear rupture. Therapeutic approaches that inhibit the ability of cancer cells to repair the nuclear disruption or that stimulate cell death after nuclear disruption could literally stop metastatic cancer cells in their tracks, with only minimal effects on healthy cells. Since nuclear disruption could also result from increased pressure inside the tumor, such approaches may even reduce tumor growth before metastasis occurs. While many of these therapies will likely take years to test and develop, our proposed experiments include evaluation of specific "stress-response" inhibitors that a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1610039
Entities
People
- Jan Lammerding
Organizations
- Cornell University
- United States Army