Abstract
Migrating cancer cells undergo repeated rupture of the protective nuclear envelope as they squeeze through small spaces in the surrounding tissue, compromising genomic integrity. Inhibiting both general DNA repair and the mechanism that seals these tears may enhance cell death and curb metastasis.
Two recent studies—from Cornell University in Ithaca, NY, and Institut Curie in Paris, France—have shown that migrating cancer cells undergo repeated rupturing of the nuclear envelope (NE) as they squeeze through tiny pores in the surrounding connective tissue. Blocking the efficient repair of these tears may enhance the cells' vulnerability and be an effective way to curb metastasis, the researchers suggest.
The NE is a protective lining that separates a cell's genetic material from its cytoplasm. “Previously, we assumed that it always stayed intact, and rupture would lead to cell death,” says Jan Lammerding, PhD, senior author of the Cornell study (Science 2016;352:353–8). “Instead, we found that up to 80% of migrating cancer cells experience repeated NE rupture and ultimately survive.”
In both studies, researchers used microfluidic technology to observe cancer cell migration and confirmed their findings in vivo using intravital imaging. Fluorescent tagging enabled them to see nuclear proteins spilling into the cytoplasm when cells squeezed through very small pores in the tissue, indicating a torn NE. These ruptures were accompanied by chromatin protrusions and DNA double-strand breaks.
Both groups reported that NE tears in migrating cancer cells, although frequent, were transient: Each time a rupture occurred, a protein complex called ESCRT III was recruited to seal the break. However, suppressing NE repair by inhibiting ESCRT III did not increase cell death; neither did inhibiting DNA repair alone. This is because when NE repair is blocked, regular DNA repair can often handle the damage caused by ruptures, explains Matthieu Piel, PhD, senior author of the Institut Curie study (Science 2016;352:359–62). Even if DNA repair is blocked, NE ruptures are so small that cells can often survive the damage. “Targeting both processes is more efficient,” he says. The researchers noted a substantial increase in the death of migrating cancer cells when both NE and DNA repair were inhibited.
These findings “represent a potential new, exciting target for therapy,” says Lance Munn, PhD, of Harvard Medical School in Boston, MA, who wasn't involved in either study. “The challenge will be to block both repair processes only in cancer cells. Otherwise you'd affect the migration of normal immune cells like leukocytes, too, and that could kill these cells, potentially antagonizing immunotherapy and leading to associated toxicity.”
Lammerding and Piel also found that NE rupture was associated with low levels of lamins—structural proteins that enable a stiff nucleus, which is necessary for cell survival. Highly invasive cancer cells have fewer lamins than normal cells, but enough to survive, Piel says, so one therapeutic possibility might be to suppress lamins even more in the former. Again, the challenge would be finding ways to do so without affecting lamin levels in normal cells.
To better translate their findings into therapeutic opportunities, the researchers are now trying to learn more about the differences between migrating cancer cells and immune cells.
“We're looking at whether metastasizing cancer cells have special properties that help them deal with this scenario of repeated damage and repair,” Lammerding says. Identifying such unique characteristics will enable the development of antimetastatic drugs that selectively target invasive cancer cells, instead of being “a sledgehammer that hits everything.” –Janet Colwell
For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.