Publisher Health

A new imaging technique for real 3D vascular ultrasound could become a key tool in strategies aimed at preventing cardiovascular disease in apparently healthy persons, complementing traditional risk parameters such as cholesterol and high blood pressure. The new results, published in JACC: Cardiovascular Imaging, show that real 3D vascular ultrasound is reliable, accurate, and faster than previous methods for the assessment of plaque volume in the carotid and femoral arteries.
The burden, or quantity, of atherosclerosis in the carotid and femoral arteries is a well-established marker of cardiovascular risk and is highlighted as a key parameter in international clinical practice guidelines and expert consensus documents. There is therefore a recognized need for better and easy-to-use methods for measuring plaque burden that can be used as population screening tools.
The new imaging method was first validated and implemented in a study of almost 200 healthy participants with an intermediate cardiovascular risk from the Athero Brain: Head-to-Heart study, led by Dr. Valentín Fuster, Director General of the Centro Nacional de Investigaciones Cardiovasculares (CNIC). The method has now been incorporated into the PESA-CNIC-SANTANDER study, also led by Dr. Fuster, where it is being used to assess more than 4000 healthy individuals over a 9-year follow-up.
The PESA-CNIC-SANTANDER study, which started in 2010 and was recently extended until 2030, is one of the most important cardiovascular prevention studies in the world.
The CNIC researchers partnered with Philips Ultrasound and Philips Research Paris-Medisys to develop a new probe and software for real 3D ultrasound to facilitate exploration of the carotid and femoral arteries and speed up quantification of atherosclerotic plaque volume. As Dr. Fuster explained, “it is clear that traditional clinical evaluations based on measurements of cholesterol, blood pressure, blood glucose, and lifestyle habits cannot, on their own, accurately determine accumulated damage in the cardiovascular system, and without this crucial information we cannot take appropriate decisions to prevent acute events such as myocardial infarction or stroke.”
The key to personalized prevention and treatment strategies, added Dr. Fuster, “is the ability to detect and quantify an individual’s accumulated cardiovascular damage, or atherosclerotic burden, using noninvasive imaging techniques.”
The newly validated 3D vascular probe incorporates 3D matrix technology, which underpins the most advanced 3D ultrasound techniques. CNIC Clinical Research Director Dr. Borja Ibáñez explained that the new technology allows simultaneous analysis by 2D and 3D ultrasound, includes all functionalities (color doppler, power-doppler, and contrast ultrasound), and is easily incorporated into daily clinical practice by technical and medical teams already experienced in ultrasound, emphasizing that “the integrated analysis software incorporates real 3D data processing.”

New research reveals factors that control the interplay of natural killer (NK) cells — which are part of the body’s innate, or first line, immune response — with tumor cells, viral infections, and solid organ transplants. The results, which are published in Science Advances and were discovered by investigators at Massachusetts General Hospital (MGH), could be used to help protect people from cancer, invading pathogens, autoimmunity, inflammatory diseases, and transplant rejection.
NK cells can effectively kill target cells in the blood, but they fail to kill infected and cancerous cells in tissues and organs like the skin, gastrointestinal tract, pancreas and breast. “This profound lack of NK cell killing function in solid organs has perplexed the field of NK cell biology for the last 60 years,” says Shawn Demehri, MD, PhD, a cancer immunologist, dermatologist and principal investigator at the MGH Center for Cancer Immunology and the Cutaneous Biology Research Center. Demehri’s work in recent years has uncovered a novel explanation for why NK cells lose their ability to kill target cells in solid organs: Organs are made of cells embedded in a dense extracellular matrix (ECM) — an elaborate matrix of proteins that form a scaffold to maintain organ structure and integrity. Interactions between NK cells and ECM proteins lead to an immediate switch in NK cell function from killer cells to helper cells when they exit the blood vessels and enter solid organs. As helper cells, NK cells produce molecules that activate and support other neighboring immune cells.
Demehri and his team postulate that NK cells’ rapid killer response in the blood and delayed helper response in tissues and organs can be explained by an evolutionary selection pressure to prolong human survival. “Infection of the blood requires immediate control by NK cells to ensure host survival; however, the suppression of a direct killer function of NK cells in the peripheral tissues may prevent over-reaction to localized insults, which could predispose the patient to excessive tissue damage and the development of chronic inflammation,” says Demehri. “Meanwhile, a helper function for the development of an overall more targeted, appropriately strong adaptive immune response may be best suited to combat viral infections in peripheral tissues.”
In this latest work involving skin transplantation and mouse melanoma models, the investigators identified collagens and elastin — major ECM proteins that are abundant in solid organs — to be the key regulators of NK cell function in tissues and cancers.
“Our fundamental discovery of how NK cells are regulated in peripheral tissues has wide-ranging implications for patients with various health conditions,” says co-lead author Maulik Vyas, PhD, a postdoctoral fellow in the Center for Cancer Immunology at MGH. “Strategies to modulate NK cell-ECM interplay in organs can provide novel therapies to combat solid cancers, viral infections, inflammatory conditions, autoimmune diseases, and fibrosis, and to improve organ transplantation.”
For example, the scientists showed for the first time that losartan, a drug that is commonly used to treat hypertension, can cause a previously resistant melanoma to become sensitive to NK cell killing by blocking collagen deposition in the tumor. The finding is significant because collagen is often abundant in solid cancers, including breast and pancreatic cancers.
“Our data strongly support the concept of blocking collagen-NK cell interactions in combination with current immunotherapies for optimal treatment of solid cancers,” says Vyas. “And our findings provide a strong rationale for future research to fully understand how ECM proteins regulate NK and other immune cell responses in health and disease. This will greatly expand the development of future therapies that exploit the interactions between ECM proteins and the immune system in the treatment of a large variety of diseases.”
Study co-authors include Mark D. Bunting, Marta Requesens, Adam Langenbucher, Erik B. Schiferle, Robert T. Manguso, and Michael S. Lawrence.
Funding was provided by the Burroughs Wellcome Fund, the Sidney Kimmel Foundation, and the National Institutes of Health.
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Materials provided by Massachusetts General Hospital. Note: Content may be edited for style and length.

While many people in wealthier countries have been vaccinated against Covid-19, there is still a need for vaccination in much of the world. A new vaccine developed at MIT and Beth Israel Deaconess Medical Center may aid in those efforts, offering an inexpensive, easy-to-store, and effective alternative to RNA vaccines.
In a new paper, the researchers report that the vaccine, which comprises fragments of the SARS-CoV-2 spike protein arrayed on a virus-like particle, elicited a strong immune response and protected animals against viral challenge.
The vaccine was designed so that it can be produced by yeast, using fermentation facilities that already exist around the world. The Serum Institute of India, the world’s largest manufacturer of vaccines, is now producing large quantities of the vaccine and plans to run a clinical trial in Africa.
“There’s still a very large population that does not have access to Covid vaccines. Protein-based subunit vaccines are a low-cost, well-established technology that can provide a consistent supply and is accepted in many parts of the world,” says J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT and a member of the Koch Institute for Integrative Cancer Research and the Ragon Institute of MGH, MIT, and Harvard.
Love and Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center (BIDMC) and a professor at Harvard Medical School, are the senior authors of the paper, which appears today in Science Advances. The paper’s lead authors are MIT graduate students Neil Dalvie and Sergio Rodriguez-Aponte, and Lisa Tostanoski, a postdoc at BIDMC.
Optimizing manufacturability
Love’s lab, working closely with Barouch’s lab at BIDMC, began working on a Covid-19 vaccine in early 2020. Their goal was to produce a vaccine that would be not only effective but also easy to manufacture. To that end, they focused on protein subunit vaccines, a type of vaccine that consists of small pieces of viral proteins. Several existing vaccines, including one for hepatitis B, have been made using this approach.

Researchers at The University of Queensland have identified a molecule essential for regulating the repair of injured nerves, which could help people recover from nerve damage.
The finding was made using the nematode worm C. elegans which has long been studied by researchers for its ability to self-repair nerve cells.
Professor Massimo Hilliard and his team at UQ’s Queensland Brain Institute (QBI) have identified that the enzyme ADM-4 is an essential protein regulating the molecular glue, or fusogen, needed for nerve repair.
“We have shown that animals lacking ADM-4 cannot repair their nerves by fusion,” Professor Hilliard said.
“ADM-4 must function within the injured neuron to stabilise the fusogen EFF-1 and allow the membranes of the separated nerves to merge.
“An exciting part of this discovery is that ADM-4 is similar to a mammalian gene, opening up the possibility that one day we may harness this process in humans.”
Study first author, Dr Xue Yan Ho, said the nematode provided a great platform for these studies.

Tumors can use an enzyme called ART1 to thwart antitumor immune cells, making the enzyme a promising new target for immunity-boosting cancer treatments, according to a study from researchers at Weill Cornell Medicine and Albert Einstein College of Medicine.
In the study, published Mar 16 in Science Translational Medicine, the researchers found strong evidence that ART1, when expressed on tumor cells, can modify a receptor on tumor-fighting immune cells in a way that triggers the death of these immune cells. In animal models of cancer, blocking ART1 increased the presence of the tumor-fighting immune cells within tumors and slowed or stopped tumor growth.
“These findings should allow us to add to our medicinal toolkit for enhancing the antitumor immune response, to benefit cancer patients,” said study co-corresponding author Dr. Timothy McGraw, professor of biochemistry and of biochemistry in cardiothoracic surgery and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
“Our main focus in this study was lung cancer, but there is evidence that this immune-evasion mechanism is at work also in other kinds of cancer,” said co-corresponding author Dr. Sandra Demaria, professor of radiation oncology and of pathology and laboratory medicine and a member of the Meyer Cancer Center at Weill Cornell Medicine.
“This is an excellent example of how translational science should work. We first found ART1 expressed in the tumors of patients with lung cancer. In the lab, we discovered that ART1 helps to block the anti-tumor immune response, specifically by inducing death of anti-tumor T cells. We then developed a therapeutic antibody that blocks the function of ART1, allows the immune system to fight the cancer and ultimately prolongs survival in tumor models,” said senior author Dr. Brendon Stiles, formerly of Weill Cornell Medicine and now chief of the Division of Thoracic Surgery and Surgical Oncology and associate director of surgical services at Montefiore Einstein Cancer Center and professor of cardiovascular and thoracic surgery at Albert Einstein College of Medicine. “Hopefully, we can very soon take that antibody back to treat our patients with cancer.”
The mammalian immune system has various safety mechanisms to prevent immune activity from becoming excessive and damaging tissues. Scientists in recent decades have come to appreciate that tumors frequently co-opt these safety mechanisms — also called immune checkpoints — to defeat natural antitumor immune responses.
That appreciation has led, in turn, to the development of “immune checkpoint inhibitor” treatments that block these safety mechanisms to enhance antitumor immunity. These treatments are now part of standard care in several types of cancer and help account for some astounding cures. However, a large proportion of individual cancers do not respond to such therapies, which hints that these cancers may make use of other, so-far-unrevealed immune checkpoint systems.
ART1 appears to be part of one such immune-checkpoint exploitation system. The researchers found that expression levels of its gene were significantly higher in the most common type of non-small-cell lung cancer (NSCLC), compared to non-cancerous lung cells. Similarly, in mice, ART1-overexpressing NSCLC tumors grew rapidly, while blocking ART1 reduced tumor growth. However, this effect on tumors appeared only in mice with intact immune systems, implying that blocking ART1 works by unleashing antitumor immunity.
Further experiments in mice with NSCLC and melanoma tumors confirmed that reducing ART1 led to a greater presence within tumors of CD8 T cells, the immune system’s most powerful weapon against cancers.
The experiments also provided strong evidence that ART1 interacts with a receptor called P2RX7R on CD8 T cells and activates signaling that causes the deaths of the CD8 T cells. The P2RX7R receptor therefore seems to be an important molecular switch that cancers use to shut down anticancer immunity.
The researchers then blocked ART1 using a humanized therapeutic antibody they had developed — in a collaboration with the Tri-Institutional Therapeutics Discovery Institute, a partnership including Weill Cornell Medicine, The Rockefeller University, and Memorial Sloan Kettering Cancer Center — and demonstrated that it slowed tumor growth and prolonged survival in mice. Dr. Stiles is now further developing the anti-ART1 antibody as a potential immune-enhancing cancer treatment.

A study published in JAMA Network Open, from the University of Minnesota, found that a common blood pressure medication — losartan — is not effective in reducing lung injury in patients with COVID-19.
This drug was investigated based on early reports suggesting benefit in preclinical models of the 2003 SARS virus, a close family member to the current SARS-CoV-2 virus. This study was conducted across 12 U.S. academic research institutions.
The U of M Medical School and School of Public Health research team sought to determine if a common blood pressure medication might decrease lung injury in patients admitted to the hospital with COVID-19. Their results found that losartan treatment did not reduce lung injury in patients admitted with COVID-19, and had no effect on mortality.
The researchers also found that critically-ill patients treated with losartan needed additional, temporary blood pressure support — though this did not lead to worse outcomes overall.
“Even though this particular drug was not effective for the treatment of COVID-19, repurposing inexpensive and relatively safe medications remains an important approach to contain healthcare costs,” said Michael Puskarich, MD, an associate professor in emergency medicine at the U of M Medical School and co-author of this study.
“Finding effective treatments for COVID-19 that can be widely used across both the developed and developing world remains an important ongoing area of investigation,” Puskarich said, who is also an emergency physician at Hennepin Healthcare.
This study was funded by the Bill and Melinda Gates Foundation. The researchers note that more studies of protein and cellular signaling from ALPS-COVID trial participants are ongoing.
“We hope that future study findings of these proteins may show insights into why the body responds the way it does to COVID-19,” said Christopher Tignanelli, MD, MS, FACS, FAMIA, an assistant professor in surgery at the U of M Medical School and co-author on this study. “Critically, this will help us understand why some people develop severe disease following COVID-19 infection and others are asymptomatic.”
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Materials provided by University of Minnesota Medical School. Original written by Kat Dodge. Note: Content may be edited for style and length.

In what they call surprise findings, Johns Hopkins Medicine scientists report that — unlike fruit flies — mosquitoes’ odor sensing nerve cells shut down when those cells are forced to produce odor-related proteins, or receptors, on the surface of the cell. This “expression” process apparently makes the bugs able to ignore common insect repellents.
In contrast, when odor sensors in fruit flies are forced to express odor receptors, it prompts flight from some smelly situations.
The findings, published Mar. 8 in Cell Reports, reveal the variation in insect olfactory systems, say the researchers, and add to the growing body of research aimed at improving methods to repel mosquitoes from human skin.
Mosquito bites not only create irritating swelling and itching, but, worldwide, they play a role in spreading rampant and often lethal diseases such as malaria and dengue fever, as well as Zika virus infections.
“When experiments don’t go as predicted, there’s often something new to be discovered,” says Christopher Potter, Ph.D., associate professor of neuroscience at the Johns Hopkins University School of Medicine, describing the new study. It turns out, he says, that, “Mosquitoes are so much trickier than we thought.”
Potter and former postdoctoral fellow Sarah Maguire, Ph.D., designed their research project suspecting they’d find that mosquitoes have the same reaction as fruit flies when their new odor sensors are forced to be expressed.

The brain is composed of billions of neurons — vulnerable cells that require a protective environment to function properly. This delicate environment is protected by 400 miles of specialized vasculature designed to limit which substances come into contact with the brain. This blood-brain barrier is essential for protecting the organ from toxins and pathogens. But in the context of neurological disease, the barrier “becomes your worst enemy,” says Anne Eichmann, PhD, Ensign Professor of Medicine (Cardiology) and professor of cellular and molecular physiology, as it also blocks the passage of therapeutic drugs.
For years, it has been the goal of neuroscientists and vascular biologists alike to find the magic bullet for temporarily opening and resealing the barrier for drug administration. Now, Eichmann’s team has developed an antibody as a tool for opening the blood-brain barrier for a couple of hours at a time, allowing for the delivery of drugs to a diseased brain. The team published its findings in Nature Communications on March 4.
“This is the first time we’ve figured out how to control the blood-brain barrier with a molecule,” says Eichmann, who is the senior author of the study.
The development and maintenance of the blood-brain barrier are dependent on what is called the Wnt signaling pathway, which regulates a number of crucial cellular processes. Eichmann’s team sought to figure out whether this pathway could be modulated to open the barrier “on-demand.”
When Kevin Boyé, a postdoctoral associate at Yale and first author of the study, joined Eichmann’s lab in 2017, he chose to study a molecule known as Unc5B, an endothelial membrane receptor expressed in the endothelial cells of capillaries. He found that if he knocked out this receptor in mice, they died early in their embryonic development because their vasculature failed to form properly, indicating that it was an important molecule in vascular development. He also discovered that a protein known as Claudin5 — which is important for creating the tight junctions between the endothelial cells of the blood-brain barrier — was also significantly reduced. This made the team realize that the receptor could be important in maintaining this barrier.
There was previously no known link between Unc5B and the Wnt signaling pathway. Through this new study, the team figured out that the Unc5B receptor controls the pathway, functioning as an upstream regulator.
Boyé then went a step further and took the receptor out in adult mice with an already established blood-brain barrier, and found that the barrier remained open in the absence of the receptor. Next, he wanted to determine which ligands — which bind to receptors and send signals between or inside cells — were responsible for the barrier effect. He discovered that one ligand, Netrin-1, also caused a blood-barrier defect when it was removed.
Next, the team developed an antibody that could block Netrin-1 from binding to its receptor. Upon injecting the antibody, the team was able disrupt the Wnt signaling pathway, causing the blood-brain barrier to open temporarily on demand.
“It was quite a fascinating journey, especially the development of our blocking antibodies,” says Boyé. “And to see that we can open the blood-brain barrier in a very time-sensitive fashion to promote drug delivery.”
Because the blood-brain barrier blocks entry to all but a tiny subset of small molecules, neurological conditions such as Alzheimer’s, multiple sclerosis, brain tumors, and depression are exceedingly difficult to treat. Having control over the barrier will be helpful for future drug delivery ventures. The team has not yet identified any potential complications, but plans to evaluate the efficacy and potential toxicity of the antibody in later research.
“This paves the way to more interesting basic research around how the body builds such a tight barrier to protect its neurons and how can it be manipulated for drug delivery purposes,” says Eichmann. “And then there’s also potential to use this as a delivery platform for drugs to penetrate into the brain.”
In future studies, the team hopes to understand how to apply its findings to chemotherapy delivery for treating brain tumors. They are also currently working to see if they can apply their antibody to other regions of the central nervous system outside of the brain.
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Materials provided by Yale University. Original written by Isabella Backman. Note: Content may be edited for style and length.

The first FDA-approved gene therapies are living drugs: immune cells taken from cancer patients engineered to target tumor cells. However, for many patients, these advanced therapies do not result in a long-lasting remission. Now, scientists at the New York Genome Center and New York University have developed a genetic screening platform to identify genes that can enhance immune cells to make them more persistent and increase their ability to eradicate tumor cells.
In the journal Nature, the researchers describe the discovery of synthetic gene programs that profoundly rewire a specific kind of immune cell called T cells, making them more effective at finding and fighting cancer cells. The research team, led by Neville Sanjana, PhD, Core Faculty Member at the New York Genome Center, Assistant Professor of Biology at New York University, and Assistant Professor of Neuroscience and Physiology at NYU Grossman School of Medicine, profiled the impact of nearly 12,000 different genes in multiple T cell subsets from human donors. The goal of this large-scale genetic screen was to identify precisely those genes that enable T cells to proliferate and to understand how those genes impact other aspects of immune cell function relevant to fighting cancer.
Previous efforts to engineer T cells have focused on the targeting of specific tumor types by careful selection of cancer or tissue-specific proteins (antigens). Since first developed more than 30 years ago, chimeric antigen receptor (CAR)-T cell therapy has proven highly effective in targeting blood cancer cells, resulting in multiple FDA-approved CAR-T therapies. CAR-T cells have antigen receptors on their surface that recognize specific proteins present on cancer cells to target and destroy them. Some patients are cancer free even a decade after their CAR-T cell therapy, as the T cells introduced years earlier are still doing their job. But one of the major challenges facing biomedical science is to understand why a large majority of cancer patients who receive CAR-T cells fail to achieve lasting remission.
Dr. Sanjana, senior author of the study, explained, “To date, genetic engineering of T cells has been focused on finding new antigens or new CARs. We took a radically different approach: Instead of changing the antibody, we thought why not try adding genes that transform T cells into more aggressive cancer fighters? These modifier genes worked very well in blood cancers, and we believe they will likely work for multiple antigens and in solid tumors.”
By combining modifier genes identified in the screen with existing CARs, the researchers were able to engineer T cells that were more effective at eliminating tumor cells. One particular modifier gene, lymphotoxin beta receptor (LTBR), acts like a molecular fountain of youth: with LTBR, T cells multiply, have a greater proportion of younger, more stem cell-like cells and resist becoming exhausted over time. Adding LTBR also caused T cells to secrete more cytokines, which are vital for the anti-tumor activity of T cells. Cytokines play an essential role in enabling T cells to better communicate with other immune cells in the body and launch coordinated attacks on the cancer. Interestingly, LTBR is not normally expressed in T cells, which highlights the power of the genome-scale screen to find genes that activate completely new cellular programs.
“Our goal was to take existing immunotherapies and make them better. We were astonished that LTBR so significantly potentiates CAR therapies. It is an important step forward towards the development of next-generation CAR-T cell therapy,” said the study’s first author Mateusz Legut, PhD, a postdoctoral fellow in the Sanjana Lab. The research team found that adding LTBR rewires the genome of T cell, triggering expression of many other genes that potentiate T cell function. The team was able to quickly understand the effects of LTBR and similar modifier genes by combining gene overexpression screens with single-cell genomics. The new method that they developed — OverCITE-seq — allowed the researchers to test the impact of different modifier genes on the cellular states of T cells, which includes the expression of every gene, the proteins decorating the cell surface, and the unique T cell receptors expressed by each cell (clonotype). OverCITE-seq gave the researchers a detailed picture of how each modifier gene boosts T cell activity and did so for all of the top-ranked genes in one single-cell experiment. For LTBR, this yielded an early clue that a large number of genes were changing, leading the researchers to further identify a well-studied modulator of gene expression called NF-kB driving many of these changes. This LTBR-driven profound reprogramming was also seen in so-called unconventional T cells such as ?? T cells, which are present at a lower abundance than conventional T cells but can target a more diverse set of tumors.
“The most exciting aspect is the demonstration that LTBR and other highly ranked genes improved the antigen-specific responses of chimeric antigen receptor T cells and ?? T cells. If validated in vitro and in clinical testing, this may have profound implication for future CAR-T cell therapies in both lymphoid malignancies and other cancers.” said study co-author Catherine Diefenbach, MD, an Associate Professor in the Department of Medicine at the Grossman NYU School of Medicine and the Director of the Clinical Lymphoma Program at NYU’s Perlmutter Cancer Center. The team also combined several top-ranked genetic modifiers with CARs similar to two existing FDA-approved therapies for blood cancers: tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta). Virtually all modifiers tested boosted CAR-T responses, including LTBR. Since T cells from cancer patients tend to be in poor condition compared to T cells from healthy donors, the researchers wanted to also test LTBR’s ability to rejuvenate cancer patient T cells. They added LTBR together with a CAR to dysfunctional T cells from patients diagnosed with diffuse large B cell lymphoma, a blood cancer, and found a similar boost in T cell function, suggesting that the technology could work as an optimized therapy in the clinic.
Andrew Sewell, PhD, an expert in T cells and immunotherapy from Cardiff University’s School of Medicine who was not involved in the study noted, “Gain-of-function screening in T cells has great potential to uncover how to make immunotherapies more successful — especially in solid cancers where current CAR T cell therapies do not work well.” The research team also showed that T cells enhanced with modifier genes were better able to eradicate not only leukemia but also pancreatic cancer cells. Those results are encouraging not only to develop a larger panel of enhanced CAR-T therapies for blood cancers, but for the key role they could play in targeting solid tumors, a field in which establishing efficient CAR-T immunotherapy has been more challenging.
In addition to Drs. Legut, Diefenbach and Sanjana, the research team included co-authors from the Sanjana lab, the NYGC Technology Innovation Lab, and the lab of Teresa Davoli, PhD, at the NYU Grossman School of Medicine. The Sanjana Lab has been focused on developing new gene editing and functional genomic technologies to reduce the high failure of current immunotherapies and build next-generation therapeutics. Since the newly-characterized modifier genes like LTBR can work hand in hand with already approved CAR-T therapies, this research has clear potential to move from bench to bedside and improve outcomes for cancer patients around the world.
Video: https://vimeo.com/687951684

Biological processes such as wound healing and cancer cell invasion rely on the collective and coordinated motion of living cells. A little understood aspect that influences these processes is the pressure differences within and between different parts of the body. Researchers from Göttingen University and Münster University designed model tumour systems using cervical cancer cells in collagen matrices to investigate whether pressure differences can push cancer cells into their surroundings. Upon embedding the model tumours into a soft matrix, an increased pressure led to a sudden burst of rapid and coordinated cellular motion that sprayed outwards from the tumour. Their results were published in Advanced Science.
The researchers designed their model system using clumps of cervical cancer cells in simple 3D tissues that they could control, enabling them to systematically study the behaviour of the cells in different pressures and environments. Usually, individual cells exert forces on their environment in order to move, and collective motion is coordinated by cell-to-cell forces because they stick and clump together. However, this new model allowed the researchers to measure other mechanisms that encourage cellular movement such as pressure differences between different regions within the body.
Using imaging techniques that allowed the scientists to follow the tumour deformation even at the level of a single cell, the researchers discovered that increased pressure in a soft matrix drove coordinated cellular motion independent of cell-to-cell stickiness by triggering cell swelling. Eight hours after the 3D clumps of cervical cancer cells were embedded in soft collagen matrices, they burst out in a sudden rapid stream of cancer cells. This fluid-like pushing mechanism exhibits high cell velocities and a sudden super-spreading motion like water spraying from a hose when you press your thumb over the top. In fact, the rapid burst seemed to kill about 80% of the cells but surprisingly the remaining cells succeeded in embedding in the same environment over the following four days, and multiplied. “This signified that after the initial burst, the remaining live cells could still divide substantially and migrate. Importantly, when this happens in a person’s body, this can prove to be extremely dangerous, often beating current cancer treatments,” explains Professor Timo Betz, Biophysics Institute, University of Göttingen.
Tumour models embedded in a stiffer collagen did not behave in the same way. In fact, even after seven days, there was a complete absence of bursts, showing that the pressure difference in the tissue was the important part of the effect. The only way that researchers could trigger the “cell burst” in stiffer collagen was by introducing weak spots in specific regions.
In this newly observed phenomenon, cell swelling in groups increased the intrinsic pressure that pushed the cancer cells out into less resistant regions of the matrix. “Such pressure-driven effects may provide primary tumours in the body an exceptional advantage: it enables them to breach the first membrane barrier and gives them the opportunity to spread to other parts of the body, or metastasize,” says Betz. He adds: “This provides new evidence that pressure-driven effects should be considered to help us better understand the mechanical forces involved in cell and tissue movement as well as cancer cell invasion. Understanding this cellular mass movement is fundamental for describing and treating cancer and similar illnesses.”
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Materials provided by University of Göttingen. Note: Content may be edited for style and length.