(Press-News.org) Cancer cells can experience stress. They have to contend with attacks by the immune system or with anti-cancer therapeutics. If they attempt to colonize other tissues, they have to break away from the extracellular matrix, enter the bloodstream and survive during the travel through the body. Then exit and start building a new colony. The ability of cells to adapt their properties to face all the challenges they encounter is called plasticity. In epithelial solid tumors, including the very common lung, breast, colon and pancreatic cancers, tumor cells plasticity hijacks a cellular development process known as epithelial-mesenchymal transition (EMT).
EMT is commonly associated to kinases - enzymes that act like a switch, turning biochemical processes on and off in cells. Scientists led by Dr. Gaetano Gargiulo at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Berlin have now discovered that another class of proteins, the chromatin modulators, plays a pivotal role in tumor cell EMT. This means they significantly influence how tumor cells change. "Our findings may help us to design therapeutic strategies to neutralize the evasion tactics of tumor cells," says lead author Michela Serresi. The study is being published in the journal Science Advances.
A combination of CRISPR and molecular reporter
EMT makes tumor cells so plastic by loosening their polarity and cell-to-cell adhesion. EMT is a cellular process by which epithelial cells are converted into mesenchymal cells. Epithelial cells have a fixed cell pole and are interconnected. Mesenchymal cells, on the other hand, are more spindle-shaped, have flexibly cell polarity and do not require intercellular adhesions. The seamless transition between epithelial and mesenchymal cells plays an important role in embryonic development. Together with the reverse process, the mesenchymal-epithelial transition, EMT enables, for example, the development of the peripheral nervous system from the neural crest during embryogenesis. Hence, this process is critical for normal cells in the human organism to take on various forms and functions. Yet as vital as EMT is, it can also be destructive. In solid cancers, for instance, it enables tumor cells to break away from the extracellular matrix and travel through the body.
The scientists were able to study the control mechanism of this process in detail by using a combination of a molecular reporter and a CRISPR interference screen. The molecular reporter is based on DNA segments that have been engineered in such a way that they produce fluoresce when complex processes take place in the tumor cells, such as when they change their cell identity. In their study, the researchers could modulate EMT in lung cancer cells using a drug and observe the change in identity through the reporter.
"Cancer cells identity changes are hardly a one-way street"
They then examined all hundreds of kinases and chromatin proteins for their ability to modulate the fluorescence reporter. Chromatin is the material of which chromosomes are composed. It enables certain genes to be on in some cells and off in others. In doing so, chromatin determines the identity of tumor cells, such as whether they are epithelial or mesenchymal. These identities are not set in stone, but can change - from the epithelial to the mesenchymal identity and vice versa. "Cancer cells identity changes are hardly a one-way street," says Gargiulo.
So if chromatin proteins determine tumor cell subtype - do they also regulate the transformation from one subtype to the other? How? And which proteins are more important? To find out, Serresi used the CRISPR gene-editing tool to snip pieces of chromatin from the cellular genes. In some cases, depending on which proteins were silenced, the tumor cells reacted by changing their identity in the epithelial or mesenchymal direction. "Chromatin proteins basically determine tumor cell plasticity, by pushing their identity in one direction or another, giving it support or shoving it away," concludes Serresi.
Kinases sound the bugle - chromatins steer the direction
Chromatins thus have a much greater influence on EMT than previously thought. "While kinases are like the gas pedal for EMT, chromatin proteins are the gearbox that controls the speed and direction of cell plasticity," says Gargiulo, summing up the process.
"This finding brings us one step closer to precision cancer therapy," says the scientist. "For it gives us an in vitro system with which we can observe not only the effects of a treatment on tumor cell survival but also on their attempt to survive by changing identity". A detailed understanding of the molecular mechanisms behind cancer cell plasticity can help developing therapeutic strategies that counteract the cancer cells' evasive maneuvers.
Dr. Michela Serresi
Team leader of the Molecular Oncology Lab
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Dr. Gaetano Gargiulo
Head of the Molecular Oncology Lab
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
The Max Delbrück Center for Molecular Medicine (MDC)
The Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) was founded in Berlin in 1992. It is named for the German-American physicist Max Delbrück, who was awarded the 1969 Nobel Prize in Physiology and Medicine. The MDC's mission is to study molecular mechanisms in order to understand the origins of disease and thus be able to diagnose, prevent and fight it better and more effectively. In these efforts the MDC cooperates with the Charité - Universitätsmedizin Berlin and the Berlin Institute of Health (BIH ) as well as with national partners such as the German Center for Cardiovascular Research and numerous international research institutions. More than 1,600 staff and guests from nearly 60 countries work at the MDC, just under 1,300 of them in scientific research. The MDC is funded by the German Federal Ministry of Education and Research (90 percent) and the State of Berlin (10 percent), and is a member of the Helmholtz Association of German Research Centers. http://www.mdc-berlin.de
Targeted radiation is often used to study and treat diverse cancer types. A multidisciplinary research team based at the University of Chicago Medicine has recently focused on a type of cell that releases a protein that enhances resistance to cancer therapies and promotes tumor progression.
The study focused on Ter cells, which are extra medullary erythroid precursers that secrete the neuropeptide artemin. In the study, published February 24, 2020, in Science Translational Medicine, the researchers showed that local tumor radiotherapy, systemic immunotherapy or the combination of both treatments were able to deplete Ter cells in the spleen, reduce artemin production and limit tumor progression both in the locally irradiated tumors as well as outside ...
Researchers believe they have closed the case of what killed the dinosaurs, definitively linking their extinction with an asteroid that slammed into Earth 66 million years ago by finding a key piece of evidence: asteroid dust inside the impact crater.
Death by asteroid rather than by a series of volcanic eruptions or some other global calamity has been the leading hypothesis since the 1980s, when scientists found asteroid dust in the geologic layer that marks the extinction of the dinosaurs. This discovery painted an apocalyptic picture of dust from the vaporized asteroid and rocks from impact circling the planet, blocking ...
COLUMBUS, Ohio - Politicization of the COVID-19 pandemic had a powerful influence over adherence to social distancing guidelines in the United States and why people did, or did not, comply during the lockdown days, a new study has found.
The analysis boiled down to whom study participants trusted most: scientists or President Donald Trump.
"People who expressed a great deal of faith in President Trump, who thought he was doing an effective job of guiding us through the pandemic, were less likely to socially distance," said Russell Fazio, senior author of the study and a professor ...
Ultra-fast, cheap LAMP-based COVID tests could be performed by non-experts at work and in public spaces, giving results in under an hour
Article Title: "Ultra-rapid detection of SARS-CoV-2 in public workspace environments"
Funding: This project was made possible through the support of a grant from Dynamic Combinatorial Chemistry, LLC, The funder provided support in the form of salaries and supplies for authors OY, ZY, JM, and BO, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific ...
Improving road safety in cities could result in a lower rate of violent crime, according to research from UCL.
Experts analysing crime and car accident data in Mexico City found a surprisingly high level of synchronicity between the two on a weekly cycle, suggesting that applying more resources to prevent road accidents would improve crime rates by enabling more efficient policing.
For the paper, published today in Cities as Complex Systems special issue in PLOS ONE, experts plotted the time and locations of nearly one million car accidents and 200,000 ...
CLEVELAND, Ohio - Researchers at University Hospitals Rainbow Babies & Children's Hospital (UH Rainbow) published new findings today that wearing a face mask - either a cloth mask or a surgical mask - did not impair the ability of subjects to get air in and out of their bodies.
The study measured heart rate, transcutaneous carbon dioxide tension, and oxygen levels in 50 adult volunteers at the conclusion of six 10-minute phases: Sitting quietly and then walking briskly without a mask; sitting quietly and then walking briskly while wearing a cloth mask; and sitting quietly and then walking ...
WATERTOWN, Mass. - Gene therapy has traditionally been conceptualized as a one-time, curative treatment option; however, research shows that there may be a need for subsequent doses years after initial treatment. While adeno-associated viral (AAV) vectors are a core part of this powerful therapeutic approach, they present two key challenges in gene therapy.
The first challenge is their immunogenicity. In gene therapy, the formation of neutralizing antibodies (Nabs) in response to AAV vector administration precludes retreatment of a patient due to the potentially dangerous immune response that would occur after a second or third administration of the therapy.
The second obstacle relates to their durability. AAV vectors ...
A new study published Feb. 24 in the journal Royal Society Open Science documents the earliest-known fossil evidence of primates.
A team of 10 researchers from across the U.S. analyzed several fossils of Purgatorius, the oldest genus in a group of the earliest-known primates called plesiadapiforms. These ancient mammals were small-bodied and ate specialized diets of insects and fruits that varied by species. These newly described specimens are central to understanding primate ancestry and paint a picture of how life on land recovered after the Cretaceous-Paleogene extinction event 66 million years ago that wiped out all dinosaurs -- except for birds -- and led to the rise of mammals.
Gregory Wilson Mantilla, a University of Washington professor of biology and curator of vertebrate ...
A research team from Skoltech and FBK (Italy) presented a methodology to derive 4D building models using historical maps and machine learning. The implemented method relies on the geometric, neighbourhood, and categorical attributes to predict building heights. The method is useful for understanding urban phenomena and changes contributing to defining our cities' actual shapes. The results were published in the MDPI Applied Sciences journal.
Historical maps are the most powerful source used to analyze changes in urban development. Nevertheless, maps represent the 3D world ...
Freshwater is accumulating in the Arctic Ocean. The Beaufort Sea, which is the largest Arctic Ocean freshwater reservoir, has increased its freshwater content by 40% over the past two decades. How and where this water will flow into the Atlantic Ocean is important for local and global ocean conditions.
A study from the University of Washington, Los Alamos National Laboratory and the National Oceanic and Atmospheric Administration shows that this freshwater travels through the Canadian Archipelago to reach the Labrador Sea, rather than through the wider marine passageways that connect to seas in Northern Europe. The open-access study was published Feb. 23 ...