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April 12, 2016
Migration creates cancer cell vulnerabilities
At a Glance
- Scientists found that migration can damage cancer cells’ nuclei and DNA, requiring repairs for their survival.
- The results may open new avenues for targeting metastatic cancer.
Cancer can arise almost anywhere in the human body. When cancer develops, old or damaged cells survive rather than dying, and new cells form when they’re not needed. These extra cells can divide without stopping and may form growths called tumors. As tumors grow, some cancer cells can break off and spread to other places in the body, a process called metastasis.
To migrate to another area, cancer cells must move through a dense scaffolding of proteins called the extracellular matrix. The cells can cut their way through by using molecular scissors, or enzymes. They can also physically contort to fit through small openings called pores. When squeezing through, cells have a limitation: the nucleus, a large structure surrounded by a protective outer lining called the nuclear envelope. The nucleus is substantially more rigid than the rest of the cell. Deforming it is risky because it houses the cell’s DNA and serves as a vital control center.
A research group headed by Dr. Jan Lammerding at Cornell University investigated what happens to nuclei as cells distort to get through the extracellular matrix. They designed a microfluidic device to watch cells move through pore sizes that mimic those in the extracellular matrix in tissues. The research was funded in part by NIH’s National Heart, Lung, and Blood Institute (NHLBI), National Institute of Neurological Disorders and Stroke (NINDS), and National Cancer Institute (NCI). Results were published online on March 24, 2016, in Science.
The researchers examined breast cancer, fibrosarcoma, and human skin fibroblast cells. As the cells squished through pores that were about the size of their nuclei or smaller, the nuclear envelopes sometimes ruptured. The chance of nuclei ripping open increased exponentially as pore sizes decreased. By labeling nuclear proteins with green and red fluorescent tags, the researchers were able to watch as the torn nuclei let proteins spill out into the cell. They saw similar results in biological environments, either using fibrillar collagen matrices or imaging cancer cells moving inside living mice.
The nuclear tears were only temporary, and the membranes closed shortly after. However, the researchers observed that DNA damage had occurred during the nuclear deformation and rupturing. Nearly 90% of cells survived despite these injuries.
Further investigation revealed that, upon rupturing, members of the ESCRT family of proteins appeared at the site of damage and resealed the nuclear membranes. Inhibiting these proteins didn’t increase cell death. Neither did blocking the cells’ DNA damage-repair machinery. But blocking both together substantially increased cell death after nuclear envelope rupture.
“Most cells in the body stay in place, and it’s presumably mostly cancer cells that are moving around,” Lammerding says. “So if we can block the mechanisms that allow them to repair themselves, then we potentially could target metastatic cancer cells.”
Metastatic cells are not the only cells that migrate throughout the body and infiltrate tissues. In order to develop treatments that avoid interfering with healthy cells, future research will be needed to identify deformation and repair properties that are unique to invading cancer cells.
—by Tianna Hicklin, Ph.D.
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Reference: Nuclear envelope rupture and repair during cancer cell migration. Denais CM, Gilbert RM, Isermann P, McGregor AL, Te Lindert M, Weigelin B, Davidson PM, Friedl P, Wolf K, Lammerding J. Science. 2016 Mar 24. [Epub ahead of print]. doi: 10.1126/science.aad7297. PMID: 27013428.
Funding: NIH’s National Heart, Lung, and Blood Institute (NHLBI), National Institute of Neurological Disorders and Stroke (NINDS), and National Cancer Institute (NCI); Department of Defense; National Science Foundation; Netherlands Science Organization; and Cancer Genomics Center, Netherlands.