In a paper published online on Jan. 18 by the journal Nature, Dana-Farber Cancer Institute researchers have mapped out a mechanism by which micronuclei could potentially disrupt the chromosomes within them and produce cancer-causing gene mutations. The findings may point to a vulnerability in cancer cells that could be attacked by new therapies.
"The most common genetic change in cancer is the presence of an incorrect number of intact chromosomes within cancer cells -- a condition known as aneuploidy," says Dana-Farber's David Pellman, MD, the study's senior author. "The significance of aneuploidy has been hard to pin down, however, because little is known about how it might trigger tumors. In contrast, the mechanism by which DNA damage and broken chromosomes cause cancer is well established -- by altering cancer genes in a way that spurs runaway cell division.
"The new study demonstrates one possible chain of events by which aneuploidy and specifically 'exiled' chromosomes could lead to cancer-causing mutations, with potential implications for cancer prevention and treatment," says Pellman, who is a Howard Hughes Medical Institute investigator and the Margaret M. Dyson Professor of Pediatric Oncology at Dana-Farber, Children's Hospital Boston and Harvard Medical School.
Whole chromosomes can end up outside the nucleus as a result of a glitch in cell division. In normal division, a cell duplicates its chromosomes and dispatches them to the newly forming daughter cells: the original set to one daughter, the twin set to the other. For a variety of reasons, the chromosomes sometimes aren't allocated evenly -- one daughter receives an extra one, the other is short one. Unlike the rest of the chromosomes, these stragglers sometimes don't make it to the nucleus. Instead, they're marooned elsewhere within the cell and become wrapped in their own membrane, forming a micronucleus.
"In some respects, micronuclei are similar to primary nuclei," Pellman remarks, "but much about their function and composition is unknown. Previous studies differ on whether micronuclei replicate or repair their chromosomes as normal nuclei do. The ultimate fate of these chromosomes is unclear as well: Are they passed on to daughter cells during cell division or are they somehow eliminated as division proceeds?"
One clue that odd-man-out chromosomes themselves may be subject to damage -- and therefore be involved in cancer -- emerged from Pellman's previous research into aneuploidy. "We found that cancer cells generated from cells with micronuclei also have a great deal of chromosome breakage," Pellman explains. But researchers didn't know if this was a sign of connection or of coincidence.
Another clue came from a recently discovered phenomenon called "chromothripsis," in which one chromosome of a cancer cell shows massive amounts of breakage and rearrangement, while the remainder of the genome is largely intact. "That finding leapt off the page of these studies -- that such extensive damage could be limited to a single chromosome or single arm of a chromosome," Pellman says. "We wondered if the physical isolation of chromosomes in micronuclei could explain this kind of highly localized chromosome damage."
To find out, Karen Crasta, PhD, of Pellman's lab and the study's lead author, used a confocal microscope to observe dividing cells with micronuclei. She found that while micronuclei do form duplicate copies of their chromosomes, the process is bungled in two respects. First, it is inefficient: part of the chromosome is replicated and part isn't, leading to chromosome damage. Second, it is out of sync: the micronucleus keeps trying to replicate its chromosomes long after replication of the other chromosomes was completed. For cell division to be successful, every step of the process must occur in the proper order, at the proper time. In fact, when study co-author Regina Dagher directly analyzed the structure of the late-replicating chromosomes, she found them to be smashed to bits -- exactly what was predicted as the first step in chromothripsis.
The final piece of the puzzle came when Pellman's colleague Neil Ganem, PhD, examined what happens to these pulverized fragments, using an imaging trick that marked the chromosome in the micronucleus with its own color.
"It has been theorized that micronuclei are garbage disposals for chromosomes that the cell doesn't need anymore," Pellman comments. "If that were true, the smashed pieces would be discarded or digested, but we found that, a third of the time, they're donated to one of the daughter cells and therefore cold be incorporated into that cell's genome.
Pellman says that the findings suggest that, unexpectedly, whole chromosome aneuploidy might promote cancer in a very similar way to other kinds of genomic alterations. The key event may be mutations in oncogenes and tumor suppressors. This mechanism may also explain how cancer cells acquire more than one such mutation at a time.
"Although chromothripsis occurs in only a few percent of human cancers, our findings suggest that it might be an extreme instance of a kind of chromosome damage that could be much more common," says Pellman, who adds that accelerating this process in cancer cells, thus generating so many mutations that the cells die, may represent a possible strategy for new therapies against certain tumors.
The research was supported by the National Institutes of Health, the Howard Hughes Medical Institute, and the Leukemia and Lymphoma Society.
Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women's Hospital as Dana-Farber/Brigham and Women's Cancer Center and it provides pediatric care with Children's Hospital Boston as Dana-Farber/Children's Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding. Follow Dana-Farber on Twitter: @danafarber and Facebook: www.facebook.com/danafarbercancerinstitute
Bill Schaller | EurekAlert!
Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute
Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.
Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
02.12.2016 | Medical Engineering
02.12.2016 | Agricultural and Forestry Science
02.12.2016 | Physics and Astronomy