Researchers at the University of Glasgow are investigating whether outcomes from heart surgery could be improved if patients were routinely tested and treated for iron deficiency.
It’s estimated that up to half of people who have heart surgery have iron deficiency, which can lead to increased blood transfusions, longer stays in intensive care and slower recovery. However, which blood test most accurately reflects iron deficiency is disputed.
Dr Pierpaolo Pellicori and his team, supported by the Glasgow Clinical Trial Unit directed by Professor John Cleland, have received British Heart Foundation (BHF) funding worth around £300,000 over three years to find out which is the best test for iron deficiency before heart surgery.
In their clinical trial, 500 people who are due to have heart surgery will have a panel of blood tests to check for iron deficiency. They will then be followed up after surgery to find out whether they needed more blood transfusions, how long they were in intensive care, and other clinical factors.
The blood results will be compared to the “gold-standard” test for iron deficiency, which is the amount of iron in the bone marrow (small fragments can be obtained during heart surgery). This will show which blood test or panel of tests is the best measure of iron deficiency.
The Glasgow researchers will also test whether giving an iron injection into a vein approximately one month before surgery gets to the bone marrow and corrects the iron deficiency – a vital first step before a larger trial to conclusively test whether a “shot” of iron before heart surgery could reduce the risk of complications and hasten recovery.
Dr Pellicori explains: “Iron deficiency affects many people who need heart surgery and it is reasonable to believe this might increase the need for blood transfusions and slow down recovery. This BHF-funded study will assess which pre-operative blood test is best for detecting iron deficiency and whether giving intravenous iron before surgery corrects the problem. This lays the foundation for a larger trial to find out who will benefit from getting a shot of iron before heart surgery.”
James Jopling, Head of BHF Scotland, said: “We’re proud to be funding this innovative research at the University of Glasgow, but we urgently need help from the public during 2021 to enable us to keep funding future medical breakthroughs like these.
“There are currently around 700,000 people in Scotland living with heart and circulatory conditions, and Covid-19 has put many of them at greater risk than ever. But the effect of the virus has also cut our ability to fund new research in half. This is the toughest challenge we’ve faced in our 60-year history and we need help now more than ever to beat heartbreak forever.”
University of Glasgow scientists are investigating how a type of white blood cell can help breast cancer to spread around the body, following major funding by research and care charity Breast Cancer Now and breast cancer research charity Secondary 1st.
As scientists across the globe are harnessing the power of immunotherapy to fight coronavirus, leading researchers at the University of Glasgow are investigating how the immune system might be used to stop breast cancer from spreading and becoming incurable.
While the pandemic is significantly impacting medical research, vital breast cancer research is continuing in Scotland under a team, led by Dr Seth Coffelt, which is investigating how the immune system, and a specific type of white blood cell, can help breast cancer to spread throughout the body, in a bid to find new ways to prevent the disease from becoming incurable.
The study, made possible by a grant from Breast Cancer Now and Secondary1st aims to understand how breast cancer tricks the immune system into helping it to grow and spread, which could eventually lead to the development of new immunotherapy treatments. This is a three year project, with the first two years already funded by breast cancer research charity Secondary 1st.
When breast cancer spreads to another part of the body (known as metastatic or secondary breast cancer) such as the bones, liver, lungs or brain, it can be controlled for some time, but currently cannot be cured. Around 1,000 people lose their lives to breast cancer every year in Scotland and secondary breast cancer is the cause of almost all of these deaths.
The immune system is the body’s major defence mechanism that seeks out and destroys foreign invaders, such as bacteria and viruses, to keep us healthy and ward off disease. In recent years, scientists have made significant breakthroughs in immunotherapy which involve reprogramming the immune system to recognise and destroy cancer cells.
New immunotherapies are already being used to treat patients with melanoma and kidney cancers, but the development of safe and effective immunotherapies for breast cancer has lagged behind.
Dr Seth Coffelt at the University of Glasgow has recently found that a type of white blood cell, called gamma delta T cells, can help breast cancer spread throughout the body by suppressing the immune system and preventing it from destroying cancer cells. He and his team believe that the breast cancer tumour may be turning these cells on, but it is not yet clear exactly how this happens.
Research over recent years has suggested that gamma delta T cells can play two roles in cancer – a cancer-supporting role and a role in protecting against cancer. The researchers hope that this project could help to identify how we can turn off the cancer-supporting function and turn on the anti-tumour function of gamma delta T cells.
Dr Coffelt’s team have also discovered that gamma delta T cells make large amounts of a molecule called NKG2D, and they are now investigating how NKG2D is turned on and what role it plays.
The researchers are studying how the behaviour of the immune system changes when breast cancer spreads to organs such as the lungs in mice. They are tracking where immune cells can be found, and whether stimulating NKG2D affects the spread of the disease.
It is hoped that this research could lead to the creation of new immunotherapies for breast cancer which can retrain gamma delta T cells and the body’s immune system to recognise and destroy cancer cells.
With the first wave of the pandemic having paused the NHS breast screening programme Breast Cancer Now estimated that around 8,600 women may have been living with undetected breast cancer, and the significant backlog of appointments is now combined with unprecedented pressures on the NHS from both the second wave and winter challenges. Research into developing new effective breast cancer treatments is therefore more important than ever as when breast cancer is diagnosed later it is harder to treat, and there is an increased risk of the disease spreading.
Dr Seth Coffelt, study lead at the University of Glasgow, said: “Nature designed gamma delta T cells to be flexible. These cells normally sense problems and alert other immune cells to danger; but breast tumours take advantage of this natural flexibility to support the spread of cancer.
“We know that breast cancer cells can communicate with gamma delta T cells and change their behaviour so that the immune system doesn’t react to cancer – understanding how cancer cells do this could open up new treatment options.
“We are very excited to receive this funding to study the interaction between breast tumours and gamma delta T cells as if we understand this our hope is that we can develop an immunotherapy that helps the immune system to recognise and get rid of cancer.”
Dr Kotryna Temcinaite, Research Communications Manager at Breast Cancer Now, which is funding the study, said: “Together with Secondary1st we are delighted to be funding this important and much-needed study into understanding how breast cancer tricks the immune system into helping it grow and spread. The coronavirus pandemic has had a huge impact on research across the country, but it is vital that we continue to do everything we can to support researchers to continue their vital work.
“Once breast cancer has spread it can be treated for some time but it can’t currently be cured. With around 1,000 people in Scotland still dying each year, we urgently need to find new ways to prevent the disease spreading and to treat it more effectively when it does.
“This research will help us to understand the molecular detail of how breast cancer can turn off the immune response, with the exciting prospect of developing new immunotherapy treatments that could turn it back on; a discovery that could stop breast cancer from spreading and ultimately reduce the number of deaths from this disease.
“Anyone concerned about the risk of their breast cancer returning or spreading can speak to our expert cancer nurses by calling our free Helpline on 0808 800 6000.”
Breast Cancer Now currently invests £2 million of funding across 12 breast cancer research projects in Scotland, all of which are working to discover how to prevent the disease, save more lives, and enable more women who have breast cancer to live well with it. To date, the charity has invested over £15 million in world-class breast cancer research in Scotland.
For more information on how Breast Cancer Now is supporting people affected by breast cancer through its support services during the pandemic, and providing hope for the future through research, please visit breastcancernow.org.
Study supports launch of Phase I clinical trial to test a designer DNA agent — an antisense oligonucleotide that targets a gene called IRF4 — in patients with multiple Myeloma.
Many patients with multiple myeloma, a type of blood cancer, eventually develop resistance to one treatment after another. That’s in part because cancer stem cells drive the disease — cells that continually self-renew. If a therapy can’t completely destroy these malignant stem cells, the cancer is likely to keep coming back.
Researchers at University of California San Diego School of Medicine and Ionis Pharmaceuticals are taking a new, targeted approach to myeloma treatment — silencing IRF4, a gene that allows myeloma stem cells and tumor cells to proliferate and survive. Past studies have shown that high IRF4 levels are associated with lower overall survival rates for patients with the disease.
In a study published January 20, 2021 in Cell Stem Cell, the team details their successes inhibiting IRF4 with an antisense oligonucleotide, an engineered piece of DNA specifically designed to bind the genetic material coding for IRF4, causing it to degrade. The oligonucleotide — an investigational antisense medicine developed by Ionis and known as ION251 — lowered disease burden, reduced myeloma stem cell abundance and increased survival of mice bearing human myeloma, according to preclinical study data.
Authors say the results support a Phase I clinical trial recently launched to assess the safety and efficacy of ION251 to treat humans with myeloma.
“As scientists, we don’t usually have direct contact with patients, as a daily reminder of what our research could do, or why it’s important,” said co-senior author Leslie Crews, PhD, assistant professor in the Division of Regenerative Medicine at UC San Diego School of Medicine. “But I’ve been working with a local support group for patients with multiple myeloma. They inspire me. They ask the most insightful questions, and it really makes it personal. I hope this work will eventually give them new potential treatments to prevent relapse, and ultimately get better.”
UC San Diego School of Medicine and Ionis Pharmaceuticals have a long history of collaborating on the development of investigational antisense medicines. Several Ionis antisense drugs have been commercially approved, including the U.S. Food and Drug Administration (FDA)-approved SPINRAZA, a therapy for spinal muscular atrophy. In addition, several other therapies are currently in clinical trials.
One challenge myeloma researchers face is that myeloma cells don’t grow well in laboratory dishes. To study the disease and test new treatments, the best method, Crews said, is to transplant human myeloma cells into mice that lack an immune system and thus won’t reject the human cells — making avatars of each unique patient, in a way.
The team tested ION251 on these myeloma mouse avatars. Compared to untreated mice, the treated mice had significantly fewer myeloma cells after two to six weeks of treatment. What’s more, 70 to 100 percent of the treated mice survived, whereas none of the untreated control mice did. There were 10 mice in each treatment or control group and they received daily doses of ION251 or a control for one week, followed by three doses per week.
In separate experiments using human cells isolated from myeloma or healthy donor samples, doses of ION251 used were enough to eradicate the myeloma stem cells while sparing healthy blood cells.
“The results of these preclinical studies were so striking that half the microscopy images we took to compare bone marrow samples between treated and untreated mice kept coming back blank — in the treated mice, we couldn’t find any myeloma cells left for us to study,” said Crews, who is also associate member of the Moores Cancer Center and member of the Altman Clinical and Translational Research Institute at UC San Diego. “It makes the science more difficult, but it gives me hope for patients.”
In addition to working on its own, the treatment improved myeloma tumor cell sensitivity to standard-of-care cancer therapeutics. The researchers also drilled down to the mechanisms at play and described the molecular effects of IRF4 inhibition — information that both clarifies how myeloma forms in the first place, and how the treatment works.
“These proof-of-principle studies will enable rapid clinical development of anti-sense oligonucleotide-mediated IRF4 inhibition to prevent myeloma relapse driven by drug-resistant cancer stem cells,” said co-senior author Catriona Jamieson, MD, PhD, Koman Family Presidential Endowed Chair in Cancer Research, deputy director of Moores Cancer Center, director of the Sanford Stem Cell Clinical Center and director of the CIRM Alpha Stem Cell Clinic at UC San Diego Health.
The Phase I clinical trial to assess the safety of ION251, sponsored by Ionis Pharmaceuticals, is now recruiting participants at Moores Cancer Center at UC San Diego Health and elsewhere. More information is available at clinicaltrials.gov/ct2/show/NCT04398485.
“This collaboration exemplifies the power of combining Ionis’ antisense technology to target previously un-druggable factors in cancer, with world-class academic, translational and clinical research from institutions such as UC San Diego to rapidly bring promising drugs to patients desperately in need,” said co-senior author A. Robert MacLeod, PhD, vice president and franchise head of Oncology at Ionis Pharmaceuticals.
According to the National Cancer Institute, multiple myeloma is the second most common blood cancer in the United States, with more than 32,000 new cases predicted in 2020 and a five-year survival of only 53.9 percent.
Additional co-authors of the study include: Phoebe K. Mondala, Ashni A. Vora, Elisa Lazzari, Luisa Ladel, Caitlin Costello, UC San Diego; Tianyuan Zhou, Xiaolin Luo, and Youngsoo Kim, Ionis Pharmaceuticals.
Funding for this research came, in part, from the National Institutes of Health (grants 1R21CA194679, R01CA205944, R01DK114468-01, 2P30CA023100-33, UL1TR001442), California Institute for Regenerative Medicine (CIRM grant TRAN1-10540), NASA (NRA NNJ13ZBG001N), LLS Blood Cancer Discoveries, Ionis Pharmaceuticals, Moores Family Foundation, Strauss Family Foundation, Koman Family Foundation, Sanford Stem Cell Clinical Center, International Myeloma Foundation, and Moores Cancer Center at UC San Diego Health.
Renewable energy sources, such as wind and solar power, could help decrease the world’s reliance on fossil fuels. But first, power companies need a safe, cost-effective way to store the energy for later use. Massive lithium-ion batteries can do the job, but they suffer from safety issues and limited lithium availability. Now, researchers reporting in ACS’ Nano Letters have made a prototype of an anode-free, zinc-based battery that uses low-cost, naturally abundant materials.
Aqueous zinc-based batteries have been previously explored for grid-scale energy storage because of their safety and high energy density. In addition, the materials used to make them are naturally abundant. However, the rechargeable zinc batteries developed so far have required thick zinc metal anodes, which contain a large excess of zinc that increases cost. Also, the anodes are prone to forming dendrites –– crystalline projections of zinc metal that deposit on the anode during charging –– that can short-circuit the battery. Yunpei Zhu, Yi Cui and Husam Alshareef wondered whether a zinc anode was truly needed. Drawing inspiration from previous explorations of “anode-free” lithium and sodium-metal batteries, the researchers decided to make a battery in which a zinc-rich cathode is the sole source for zinc plating onto a copper current collector.
In their battery, the researchers used a manganese dioxide cathode that they pre-intercalated with zinc ions, an aqueous zinc trifluoromethanesulfonate electrolyte solution and a copper foil current collector. During charging, zinc metal gets plated onto the copper foil, and during discharging the metal is stripped off, releasing electrons that power the battery. To prevent dendrites from forming, the researchers coated the copper current collector with a layer of carbon nanodiscs. This layer promoted uniform zinc plating, thereby preventing dendrites, and increased the efficiency of zinc plating and stripping. The battery showed high efficiency, energy density and stability, retaining 62.8% of its storage capacity after 80 charging and discharging cycles. The anode-free battery design opens new directions for using aqueous zinc-based batteries in energy storage systems, the researchers say.
How are galaxies able to keep forming stars and planets? Astronomers from Texas Christian University are using the Green Bank Telescope to reveal more about this process, studying high-velocity clouds that are being pulled into our Milky Way galaxy by its gravitational pull.
Stars and planets require large amounts of gas to form, and galaxies can run out of this cosmic building material unless they can capture more gas from their surroundings. Obstacles in the way can disrupt and disperse clouds before they conclude their journey.
Texas Christian University physics and astronomy professor Dr. Kat Barger led a team observing Complex A, a high velocity gas cloud containing enough material to make more than 2 million Suns – if all of it could reach our Milky Way. However, gas instabilities form along the cloud as parts of it drip through the lower density halo gas that surrounds it. These drips are then sheared off as the high velocity cloud rubs against the halo gas that it is traveling through–essentially acting like a wind tunnel. Gradually, these clouds lose their valuable star and planet building material. Dr. Barger’s team is deciphering how large galaxies like ours will be able to keep making stars and planets over the next billion years to come.
Astronomers are simulating these gas instability processes that affect these clouds, “Simulations keep getting better, with higher resolution and more physics, but they are still poorly constrained. We still don’t know the details of how exactly these clouds break up, but these observations will help,” says Dr. Barger.
The Green Bank Telescope is an important part of capturing this information. Observations of gas clouds like Complex A, mapped at a high resolution, have only been completed once before. The Green Bank Telescope sensitivity and capacity make research like this possible. Collaborator Dr. David Nidever says that this telescope allows “us to map this large gas cloud in great detail down to the minute undulating features being produced by it’s path onto the Milky Way’s disk”. Dr. Barger is pleased with their progress, “This is the first time that we’ve mapped a gas cloud that did not originate from the Milky Way and that will supply our galaxy with new gas so thoroughly.”
The study was carried out by experts from the Universities of Nottingham and Manchester and Imperial College London, along with the Diamond Light Source – the UK’s national synchrotron science facility.
Glulisine is a rapid-acting synthetic insulin developed by Sanofi-Aventis – with a trade name of Apidra. It is used to improve blood sugar control in adults and children with diabetes.
In this new study, scientists set out to establish the exact structure of gluisine, and how this structure might affect the way in which it behaves physiologically.
The team aimed to establish, by examining the structure, what fundamental role gluisine plays in diabetes management. These findings could potentially lead to an improved synthetic insulin for patients, with fewer side effects.
“For the first time, our research provides novel, structural information on a clinically relevant synthetic insulin, glulisine, which is an important treatment for those patients presenting with diabetes. This information sheds light on the dissociation of glulisine and can explain its fast dissociation to dimers and monomers and thereby its function as a rapid-acting insulin. This new information may lead to a better understanding of the pharmacokinetic and pharmacodynamic behaviour of glulisine and, in turn, might assist in improving its formulation and reducing side effects of this drug.” — said Dr Gary Adams Associate Professor and Reader in Applied Diabetes Health at the University of Nottingham, and lead author of the study.
To carry out the research, the team created a perfect crystal of glulisine (see figure 1).
The researchers then applied a combination of methods to provide a detailed insight into the structure and function of glulisine.
Dr Hodaya Solomon, a member of the Imperial College team, and joint first author said: “The key molecular level comparisons between this crystal structure of glulisine and of previous insulin crystal structures showed that a unique position of the glutamic acid (an amino acid), not present in other fast-acting analogues, pointed inwards rather than to the outside surface. This reduces interactions with neighbouring molecules and so increases preference of the more-active-for-patients dimer form, giving the experts a better understanding of the behaviour of glulisine”.
John Helliwell, Emeritus Professor of Chemistry at the University of Manchester, and one of the authors of the paper, said: “An unexpected finding was that the glulisine formulation is documented as a zinc-free insulin analogue for its rapid absorption action. Insulin crystallography has shown that zinc is pivotal for hexamer formation. The new glulisine crystal structure showed zinc bound in the same way as in native insulin, by three histidine amino acids. This finding must mean that traces of zinc ions are present in the commercial, as supplied, formulation solution. A further optimisation for glulisine is now clear, that of finally removing the zinc.”
The study was funded by the Independent Diabetes Trust.
A study by LMU researchers shows that putatively immature dendritic cells found in young children are able to induce robust immune responses. The results could lead to improved vaccination protocols.
Dendritic cells are a vital component of the innate immune system, which constitutes the body’s first line of defense against infectious agents and tumor cells. Their job is to activate the T-cell arm of the adaptive immune system, which confers specific and long-lasting protection against bacterial and viral infections. Dendritic cells engulf and degrade proteins that signal the presence of invasive pathogens. The resulting fragments (antigens) are displayed on their surfaces. T cells bearing the appropriate receptors are then activated to seek out and eliminate the pathogen. Newborns and young children have fewer dendritic cells than adults, and these juvenile cells also carry fewer antigen-presenting complexes on their surfaces. Based on these observations, immunologists have generally assumed that these cells are functionally immature. However, new work published by a research team led by Professor Barbara Schraml at LMU’s Biomedical Center has shown – using the mouse as a model system – that this assumption is in fact erroneous. Although early dendritic cells differ in their characteristics from those of mature mice, they are nevertheless quite capable of triggering effective immune reactions. The new findings suggest ways of boosting the efficacy of vaccines for young children.
With the help of fluorescent tags attached to specific proteins of interest, Schraml and her colleagues traced the origins and biological properties of dendritic cells in newborn and juvenile mice, and compared them with those of mature animals. These studies revealed that dendritic cells are derived from different source populations, depending on the age of the animal considered. Those found in neonatal animals develop from precursor cells produced in the fetal liver. As the mice get older, these cells are progressively replaced by cells arising from myeloid precursors, a class of white blood cells that originates from the bone marrow. “However, our experiments demonstrate that – in contrast to the conventional view – a particular subtype of dendritic cells named cDC2 cells is able to activate T-cells and express pro-inflammatory cytokines in young animals,” Schraml explains. “In other words, very young mice can indeed trigger immune reactions.”
Nevertheless, early cDC2 cells differ in some respects from those found in adult mice. For example, they show age-dependent differences in the sets of genes they express. It turns out that these differences reflect the fact that the signaling molecules (‘cytokines’) to which dendritic cells respond change as the mice get older. “Among other things, the array of receptors that recognize substances which are specific to pathogens changes with age,” says Schraml. “Another surprise for us was that early dendritic cells activate one specific subtype of T-cells more effectively than others. Interestingly, this subtype has been implicated in the development of inflammatory reactions.”
The results of the study represent a substantial contribution to our understanding of the functions of dendritic cells, and they could have implications for medical immunology. The immune system of newborns differs from that of more mature individuals insofar as immune responses in early life tend to be weaker than those invoked later in life. “Our data suggest that it might be possible to enhance the efficacy of vaccinations in childhood by, for example, adapting the properties of the immunizing antigen to the specific capabilities of the juvenile dendritic cells,” says Schraml.
The drug Remdesivir only weakly inhibits the new coronavirus SARS-CoV-2. Research groups from Göttingen and Würzburg have discovered why this is so.
Remdesivir is the first drug against Covid-19 to be conditionally approved in Europe and the United States. The drug is designed to suppress the rapid replication of the SARS-CoV-2 virus in human cells by blocking the viral copying machine, called RNA polymerase.
Researchers at the Max Planck Institute (MPI) for Biophysical Chemistry in Göttingen and the University of Würzburg have now elucidated how remdesivir interferes with the viral polymerase during copying and why it does not inhibit it completely. Their results explain why the drug has a rather weak effect. (Nature Communications, January 12, 2021)
“After complicated studies, we come to a simple conclusion,” Max Planck Director Patrick Cramer says. “Remdesivir does interfere with the polymerase while doing its work, but only after some delay. And the drug does not fully stop the enzyme.”
RNA duplication is a colossal task
At the pandemic’s beginning, Cramer’s team at the MPI for Biophysical Chemistry had elucidated how the coronavirus duplicates its RNA genome. For the pathogen this is a colossal task as its genome comprises around 30,000 RNA building blocks, making it particularly long.
To elucidate remdesivir’s mechanism of action, Cramer’s team collaborated with Claudia Höbartner’s group. The latter produced special RNA molecules for the structural and functional studies. “Remdesivir’s structure resembles that of RNA building blocks,” explains Höbartner, a professor of chemistry at the University of Würzburg. The polymerase is thereby misled and integrates the substance into the growing RNA chain.
Pausing instead of blocking
After remdesivir had been incorporated into the viral genome, the researchers examined the polymerase-RNA complexes using biochemical methods and cryo-electron microscopy. They discovered that the copying process pauses precisely when three more building blocks have been added after remdesivir was incorporated into the RNA chain.
“The polymerase does not allow the installation of a fourth one. This pausing is caused by only two atoms in the structure of remdesivir that get hooked at a specific site on the polymerase.
However, remdesivir does not fully block RNA production. Often, the polymerase continues its work after correcting the error,” explains Goran Kokic, a research associate in Cramer’s lab, who together with Hauke Hillen, Dimitry Tegunov, Christian Dienemann, and Florian Seitz, had conducted the crucial experiments. They all are first authors of the publication about this work recently published in the scientific magazine Nature Communications.
Improving remdesivir and its effect
Understanding how remdesivir works opens up new opportunities for scientists to tackle the virus. “Now that we know how remdesivir inhibits the corona polymerase, we can work on improving the substance and its effect. In addition, we want to search for new compounds that stop the viral copying machine,” Max Planck Director Cramer says.
“The vaccinations now underway are essential to bring the pandemic under control. But we also need to develop effective drugs that mitigate Covid-19 disease progression in the event of infection.”
Reference: Goran Kokic, Hauke Sven Hillen, Dimitry Tegunov, Christian Dienemann, Florian Seitz, Jana Schmitzova, Lucas Farnung, Aaron Siewert, Claudia Hoebartner, Patrick Cramer: Mechanism of SARS-CoV-2 polymerase inhibition by remdesivir. Nature Communications 12, 279 (2021), doi: 10.1038/s41467-020-20542-0
How do tumours develop in the cervix? Many new details are now known about this question. This is also thanks to Dr. Cindrilla Chumduri from the Biocentre at the University of Würzburg.
Organoids are increasingly being used in biomedical research. These are organ-like structures created in the laboratory that are only a few millimetres in size. Organoids can be used to study life processes and the effect of drugs. Because they closely resemble real organs, they offer several advantages over other cell cultures.
Now there are also organoid models developed for the cervix. This part of the female body is particularly at risk to develop cancers. By creating novel organoid models, a group led by Cindrilla Chumduri (Würzburg), Rajendra Kumar Gurumurthy (Berlin) and Thomas F. Meyer (Kiel) have established a unique approach to studying the biology of the cervix and identify key turning points in cancer development.
In results published in the journal Nature Cell Biology, the researchers used the organoids to identify stem cells of the healthy cervix and the changes that arise during metaplasia, an early stage of carcinogenesis.
How precancerous cells develop
The cervix consists of two regions covered by different types of epithelial cells: multilayered squamous and single-layered columnar epithelia that merge at transition zones. These transition zones are hot spots for infection-induced cancer development.
However, an important precancerous condition at these sites is the occurrence of metaplasia, a process whereby the non-resident epithelium replaces the resident epithelium. The researchers have now revealed the origin of these metaplastic cells and how they are regulated.
For the first time, the researchers have created a complete cellular atlas of the uterine cervix. They discovered that the stratified and columnar epithelia at the cervical transition zone arise from two distinct stem cells. The regeneration of these two epithelial lineages and their homeostasis at the transition zone are controlled by opposing Wnt signals from the underlying stromal compartments.
The researchers also showed how quiescent stem cells are activated, that eventually develop into squamous metaplasia replacing resident columnar epithelium. Among other things, they showed that adenocarcinomas and squamous cell carcinomas arise from different stem cell lineages.
This pioneering and comprehensive finding in this study provides critical insights into the cervix biology and the transition points between the healthy and early event of carcinogenesis.
Research on cancer-causing viruses and bacteria
“These fundamental findings form a basis for further understanding of the mechanisms involved in carcinogenesis at these metaplastic sites. To study how human papillomavirus (HPV), together with superseding bacterial infections, plays a key role in transforming cells to malignancy. Additionally, these critical insights can help to develop diagnostics for the early detection of these two tumor forms and new therapeutic strategies,” says Dr Cindrilla Chumduri.
The scientist has been leading a research group at Julius-Maximilians-Universität (JMU) Würzburg since 2019, based at the Biocentre, Chair of Microbiology. Prior to that, she conducted research in Berlin for eight years, first at Max Planck Institute for Infection Biology, then at Charité Universitätsmedizin.
At JMU, the researcher has found an excellent environment for her work. Her research focuses on understanding the interaction of pathogenic microbes and the host tissue at different stages of cancer development. At JMU, Dr Chumduri continues to use organoid models to decipher mechanisms of carcinogenesis induced by pathogens.
The work described here was funded by the German Federal Ministry of Education and Research (BMBF) through the Infect-ERA project CINOCA, and by the German Research Foundation (DFG), Graduiertenkolleg 2157.
Reference: Cindrilla Chumduri, Rajendra Kumar Gurumurthy and Thomas F. Meyer, “Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia, Nature Cell Biology, 18 January 2021, DOI: 10.1038/s41556-020-00619-0