Nuclear stiffness keeps stem cells, cancer cells in place

Adult stem cells and cancer cells have many things in common, including an ability to migrate through tiny gaps in tissue. Both types of cells also experience a trade-off when it comes to this ability; having a flexible nucleus makes migration easier but is worse at protecting the nucleus' DNA compared to a stiffer nucleus. Nuclear proteins that regulate nuclear stiffness are therefore thought to control processes as diverse as tissue repair and tumor growth.

In a study published in the Journal of Cell Biology, researchers at the University of Pennsylvania have shown that cell migration through micron-size pores is regulated by lamin-A, a nuclear protein that is very similar to the fibrous ones that make up hair.

They have also shown that a cell's ability to survive the mechanical stress of migration depends on proteins called "heat shock factors." Using an anti-cancer drug that inhibits heat shock responses, they showed that this drug's effectiveness relies on inhibiting the invasive migration of cells via the same mechanism.

Taking into account the role that lamin-A plays in increasing nuclear stiffness could help stem cell biologists and cancer clinicians interpret the diversity of nuclear shapes seen in a static sample of tissue under a microscope. Nuclei normally appear rounded but can also appear multi-lobed or greatly elongated; high lamin-A levels tend to produce the more distorted shapes after a cell squeezes its nucleus through a narrow pore.

"If we can understand more clearly the effects the lamin-A meshwork within nuclei has on the ability of cells to crawl through tiny openings," said Dennis Discher, professor in the Department of Chemical and Biomolecular Engineering in the School of Engineering and Applied Science, " then we can develop better nucleus-directed treatments for stopping the spread of cancer or for keeping stem cells in the right place while they grow into tissue."

Discher, along with lead author Takamasa Harada, a graduate student in his lab, conducted the studies with fellow lab members Joe Swift, Jerome Irianto, Jae-Won Shin, Kyle Spinler, Avathamsa Athirasala, Dave Dingal and Irena Ivanovska, as well as undergraduate student Rocky Diegmiller.

The study's experiments were conducted on immortalized human cancer cells as well as human-donor-derived mesenchymal stem cells, which are in wide use in clinical trials for tissue repair. The researchers either inhibited or overexpressed lamin-A in the cells, then placed both kinds on top of a thin sheet with very small pores. By adding blood serum to a chamber on the bottom of the porous sheet, the researchers encouraged the cells to push, pull and squeeze their nuclei through the pores.

Looking under a microscope at the cells that made it though the sheet revealed very few of the cells where lamin-A had been overexpressed. There was also a dearth of cells where lamin-A was strongly repressed. The cells that were most successful in migrating through the sheet's pores were the ones with lamin-A only slightly less than normal.

"The decreased migration with very low lamin-A levels was especially surprising," Harada said, "and so we measured the physical stiffness of the various nuclei, confirming that cell nuclei were systematically softer with low levels of lamin-A."

"While cells with stiffer nuclei are clearly unable to push or pull their nuclei through the pores," he said, "all of the softer nuclei could be moved through more easily, which presented a paradox."

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Nuclear stiffness keeps stem cells, cancer cells in place