Navigation Links
Penn researchers show nuclear stiffness keeps stem cells and cancer cells in place
Date:2/25/2014

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."

To resolve the paradoxical decrease in cell number with very soft nuclei, the researchers saw that the cells on the bottom of the porous sheet turned on a marker for cell death that was otherwise absent from cells on top and the lower the lamin-A the greater the number of dying cells. As a cell squeezes its nucleus through a small pore, cell death is triggered and more so when lamin-A is low.

"Moderate decreases in lamin-A allow more cells to migrate and live," Discher said, "but, when lamin-A is too low, death dominates migration. The narrow pore becomes a torture chamber for the DNA. We were bewildered by this and analyzed hundreds of proteins for some clue, discovering that another stress response pathway is deficient when lamin-A is very low. The heat shock proteins are famous for being turned on by high temperature stress to protect DNA and the rest of the cell, and the underlying gene circuitry somehow turns off when lamin-A is made artificially low."

The researchers showed that treating cells that have normal levels of lamin-A with a drug that inhibits heat shock proteins had the same effect as reducing lamin-A levels. The findings provide a better fundamental understanding of the roles of nuclear stiffness and stress resistance and could underpin other treatments as well.

"There really were no previous studies showing that the nucleus in stem cells and cancer cells could have such a prominent role in cell trafficking," Discher said. "And, since we confirmed some of our cell culture observations by studying human tumor growth in mice, this very physical mechanism must apply to human tissue as well. Nuclear stiffness is a property that should also help keep stem cells anchored in their niche until tissue is damaged to release the cells."


'/>"/>

Contact: Evan Lerner
elerner@upenn.edu
215-573-6604
University of Pennsylvania
Source:Eurekalert  

Related medicine news :

1. CWRU researchers find byproducts of bacteria-causing gum disease incite oral cancer growth
2. Researchers make the invisible visible
3. Researchers look for culprit behind oral health problems in HIV-positive patients
4. Clemson researchers develop sticky nanoparticles to fight heart disease
5. NUS researchers make new discovery of protein as a promising target for treatment of ATC
6. Scripps researchers recommend mobile compression device to prevent DVT after joint surgery
7. No such thing as porn addiction, researchers say
8. LA BioMed researchers report on promising new therapy for devastating genetic disorder
9. NIH-funded researchers use antibody treatment to protect humanized mice from HIV
10. Researchers blend orthopedics, engineering to better repair torn rotator cuffs
11. Researchers discover new hormone receptors to target when treating breast cancer
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Penn researchers show nuclear stiffness keeps stem cells and cancer cells in place
(Date:2/9/2016)... Fort Worth, Texas (PRWEB) , ... February 09, ... ... restoration and reconstruction firm helping businesses recover after a disaster, announced today the ... restoration service companies in Hawaii. , “Investing in like-minded companies who ...
(Date:2/9/2016)... Charlotte, NC (PRWEB) , ... February 09, 2016 ... ... support the launch and production of its newest mobility device, the StandUp Walker. ... innovations in walker design in the last 50 years. , StandUp Walker’s novel ...
(Date:2/9/2016)... ... February 09, 2016 , ... Cirracore Enterprise Cloud, today ... workloads to the cloud. Cirracore provides a secure VMware® vCloud Air based ... Internet. Transformation Solutions (TSL Partners) provides a full range of services from ...
(Date:2/9/2016)... FL (PRWEB) , ... February 09, 2016 , ... ... innovative specialty pharmacies, announces today the continuation of the ‘Pay It Forward’ program ... each prescription referral received at our specialty pharmacy. , “Since our Pay ...
(Date:2/9/2016)... ... February 09, 2016 , ... On January 12, 2016 Paul McElwee, ... after they noticed their furnace not producing any heat. Shortly after entering the home, ... heat exchanger was leaking dangerous levels of carbon monoxide into the home, at 2,000 ...
Breaking Medicine News(10 mins):
(Date:2/9/2016)... 9, 2016 QGEN ... den Abschluss eines Kooperationsvertrags mit 10x Genomics ... in den Bereichen Next-Generation-Sequencing (NGS), Single-Cell-Biology und ... Frankfurt Prime Standard: QIA) gab heute den ... die Entwicklung und Förderung umfassender Lösungen in ...
(Date:2/9/2016)... 2016   AllCare Plus Pharmacy announced today ... of Approval ® for Home Care Accreditation ... The Gold Seal of Approval ® is a ... providing safe and effective care.  ... a rigorous on-site survey in January 2016. The survey ...
(Date:2/9/2016)... 9, 2016 The leader in accelerated orthodontics, ... is the recipient of the 2015 Townie Choice ... Class II medical device that speeds up orthodontic tooth ... pain often associated with treatment, AcceleDent was selected by ... annual Orthotown survey of the most reliable ...
Breaking Medicine Technology: