Stiffness drives cancer invasion through previously unknown mechanism
Researchers at the University of California, San Diego School of Medicine and Moores Cancer Center have discovered a molecular mechanism that connects breast tissue stiffness to tumor metastasis and poor prognosis. The study, published April 20 in Nature Cell Biology, may inspire new approaches to predicting patient outcomes and halting tumor metastasis.
"We're finding that cancer cell behavior isn't driven by just biochemical signals, but also biomechanical signals from the tumor's physical environment," said senior author Jing Yang, PhD, associate professor of pharmacology and pediatrics.
In breast cancer, dense clusters of collagen fibers makes the tumor feel stiffer than surrounding tissue. That's why breast tumors are most often detected by touch -- they feel harder than normal breast tissue. But it's also known that increased tumor stiffness correlates with tumor progression and metastasis, as well as poor survival.
To determine how tissue stiffness influences tumor behavior, the team of cancer biologists and bioengineers used a hydrogel system to vary the rigidity on 3D cultures of breast cells from that typically experienced by normal mammary glands to the high stiffness characteristic of breast tumors. They discovered that high stiffness causes a protein called TWIST1 to lose its molecular anchor and move into the cell's nucleus. In the nucleus, TWIST1 activates genes that enable breast cancer cells to invade surrounding tissue and metastasize to other places in the body.
The researchers also compared mouse models of human breast cancer with and without TWIST1's anchor, a protein called G3BP2. Without G3BP2, tumors were more invasive and developed more metastases in the lung, compared to tumors with G3BP2.
The same mechanism plays out in human breast cancers, too, the researchers found. Analysis of human breast cancer patient samples showed that patients with stiffer tumors (meaning tumors with more organized collagen structures) did not survive as long as patients with more compliant tumors with disorganized collagen. Patients with both low G3BP2 and stiffer tumors had even shorter survival times. The correlations were so clear the team could use these factors -- G3BP2 protein levels and collagen organization -- to predict patient outcome.
"Next we want to understand exactly how cells interpret mechanical cues into biological responses," said Laurent Fattet, PhD, a postdoctoral researcher in Yang's lab who led the study, along with former graduate student Spencer Wei. "This cross-talk between a tumor's biomechanical microenvironment and the inter-workings of individual cancer cells may someday provide new therapeutic strategies to slow cancer's spread."
Co-authors of this study also include Jeff H. Tsai, Vincent H. Pai, Hannah E. Majeski, Albert C. Chen, Robert L. Sah, and Adam J. Engler, UC San Diego; Yurong Guo, and Susan S. Taylor, Howard Hughes Medical Institute and UC San Diego.
This research was funded, in part, by the National Institutes of Health (grants DP2OD002420-01, 1RO1CA168689, 1R01CA174869, DK54441, P01AG007996, 2T32CA067754, 5T32CA077109), Department of Defense Breast Cancer Program, American Cancer Society, Howard Hughes Medical Institute, ARCS Foundation and Fondation pour la Recherche Médicale.
Heather Buschman | EurekAlert!
Researchers release the brakes on the immune system
18.10.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn
Norovirus evades immune system by hiding out in rare gut cells
12.10.2017 | University of Pennsylvania School of Medicine
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
17.10.2017 | Event News
10.10.2017 | Event News
10.10.2017 | Event News
18.10.2017 | Materials Sciences
18.10.2017 | Physics and Astronomy
18.10.2017 | Physics and Astronomy