Researchers Pinpoint How PARP Inhibitors Combat BRCA1 and BRCA2 Tumor Cells (Medicine)

Key Takeaways

  • PARP inhibitors, used to treat patients with cancer of the breast, ovaries, prostate and pancreas, work by inducing persistent DNA gaps in tumor cells with BRCA1 and BRCA2 mutations.
  • The discovery offers the potential to monitor tumors for the development of resistance to PARP inhibitor therapy, and to identify drug combinations that could prevent drug resistance and improve the efficacy of cancer therapies.

This work finally explains why PARP inhibitors kill BRCA-mutant cells selectively.

— Zou Lee, PhD, Scientific co-director, Mass General Cancer Center 

A team of Massachusetts General Hospital (MGH) researchers has discovered how an important class of anti-cancer drugs called PARP inhibitors works, a finding that could help improve treatment and prolong survival for patients with breast cancer and other malignancies.

PARP (poly[ADP-ribose] polymerase) inhibitors such as olaparib (Lynparza), rucaparib (Rubraca) and niraparib (Zejula) are used to treat patients with cancers of the breast, ovaries, prostate and pancreas, and are particularly effective against tumors carrying mutations in the BRCA1 and BRCA2 tumor suppressor genes.

PARP inhibitors, like many other classes of anti-cancer drugs, are known to work by interfering with the ability of cancer cells to repair themselves after experiencing damage to their DNA, but exactly how PARP inhibitors selectively kill cancer cells was poorly understood.

But as Zou Lee, PhD, and colleagues found, PARP inhibitors work by creating gaps in tumor-cell DNA that remain present through multiple cell cycles (the process by which cells replicate: grow, divide, repeat). They also found that BRCA1/2 mutant cancer cells cannot respond to these gaps and therefore fail to repair properly, leading to the death of tumor cells. 

These findings provide a mechanistic explanation of the selectivity of PARP inhibitors toward cancer cells, and they also offer new opportunities to improve the use of PARP inhibitors in the clinic,” says Zou, scientific co-director of the Mass General Cancer Center and the Center for Cancer Research, and professor of Pathology at Harvard Medical School.

“This work finally explains why PARP inhibitors kill BRCA-mutant cells selectively,” he adds.

The research findings by Zou and colleagues Antoine Simoneau, PhD, and Rosalinda Xiong, both from the MGH Department of Pathology, are published in the journal Genes and Development.

The discovery has the potential to help clinical researchers better identify cells that are sensitive to PARP inhibitors, and to indentify potential mechanisms by which cancer cells may develop resistance to PARP inhibitors, Zou says.

“We can actually monitor BRCA-mutant cells during PARP inhibitor therapy, and then watch them if they change during the therapy, and then we can predict when they will become resistant to the drugs,” he explains.

Zou and colleagues propose development of a clinical test to determine whether BRCA-mutant cells are slowing in growth in the second cell cycle during PARP inhibitor treatment.

“We think that this slowdown is the reason for the development of resistance to PARP inhibitors. If the cells don’t slow down, they should be sensitive to the drugs, but if they do slow down they may be developing resistance,” he says.

Because the ability of BRCA-mutant cells to slow down and thus develop resistance to PARP inhibitors is dependent on a master checkpoint protein (kinase) labeled ATR, it should be possible to combine PARP inhibitors with another class of drugs in development that are designed to inhibit ATR, thereby preventing resistance to PARP inhibitors.

The work is supported by grants to Zou from the National Institutes of Health.

Reference: Antoine Simoneau, Rosalinda Xiong, Lee Zou. The trans cell cycle effects of PARP inhibitors underlie their selectivity toward BRCA1/2-deficient cells. Genes & Development, 2021; DOI: 10.1101/gad.348479.121

Provided by Massachusetts General Hospital

A Leap in Understanding Hypertrophic Cardiomyopathy (Medicine)

Hypertrophic cardiomyopathy (HCM) is the most common of all genetic heart diseases and is the leading cause of sudden cardiac death. HCM is characterized by an abnormal thickening of the heart muscle, which, over time, can lead to cardiac dysfunction and, ultimately, heart failure. 

A paper published June 15 in the Proceedings of the National Academy of Sciences (PNAS) and co-authored by Beth Pruitt, UC Santa Barbara professor of mechanical engineering and director of the UCSB Institute for BioEngineering, describes the results of a complex long-term collaboration that has included researchers at Stanford University, the University of Washington, and the University of Kentucky. The study has led to new understanding of how genetic mutations play out at the cellular level to cause HCM, and new perspectives on how to prevent it.

In the paper, titled “Hypertrophic cardiomyopathy β-cardiac myosin mutation (P710R) leads to hypercontractility by disrupting super-relaxed state,” the authors explain that more than one thousand genetic mutations that cause HCM have been identified. The majority of them are found in genes that encode sarcomeric proteins, the structural building blocks of heart muscle responsible for generating and regulating contraction and relaxation. Roughly a third of the mutations are located in β-cardiac myosin, the primary protein that drives contraction of the heart cells.

Contraction of the heart muscle, and every other muscle in our bodies, results from a process in which the motor protein myosin “walks” along a chain of actin molecules, a process known as the cross-bridge cycle. During this process, chemical energy in the form of ATP is converted to mechanical energy, ultimately leading to cardiac contraction. 

Prior to a contraction, the head of one strand of an intertwined two-strand myosin molecule is tucked up against an actin molecule. Muscle contraction is initiated when a molecule of ATP, known as the “energy currency” of biological systems, binds to the myosin head. The myosin head, and the attached ATP, then detaches from the actin, initiating hydrolysis of the ATP, which is transformed into ADP plus a phosphate group. That process releases energy that “cocks” the myosin protein into a high-energy state and changes the shape of the myosin so that it is ready to crawl along the actin. At that point, the phosphate is released from the myosin, causing the myosin to push on the actin and release the phosphate, which leads the myosin to walk to the next chain of actin and contract the muscle. All of this, involving millions of heads of myosin walking across actin in steps that take microseconds to complete, must occur at the proper rate in order to maintain heart health.
Because HCM is often observed in patients having mutations in the β-cardiac myosin protein, it had been hypothesized that HCM mutations cause a cascade of events that manifest, ultimately, in damage to the heart itself. This study put that idea to the test, focusing on a single mutation, P710R, which dramatically decreased in vitro motility velocity — the rate at which the myosin motor walks on actin — in contrast to other MYH7 mutations, which led to increased motility velocity. 

The overarching research question of this project was to learn how a mutation linked to heart disease in patients changes heart function at a cellular level.

The team used CRISPR technology to edit human induced pluripotent derived stem cell cardiomyocytes (cells responsible for heart contraction) by inserting the P710R mutation into them. Pruitt leads the stem cell bank at UCSB, where “clean” cell lines, having no genetic abnormalities, are maintained and reproduced for university researchers. Such clean, mutation-free lines provide a perfect benchmark for comparison with cells to see very precisely the effects of the P710R mutation. For example, the research team is now testing the effects of different mutations linked to heart disease in the same genetic background.

 “You can have ten people with the same gene mutation in this protein, and they can have varying degrees of clinical significance, because the rest of their genome is different; that’s what makes us individuals,” Pruitt says. “These lines let us examine what is a result of the genetic mutation. By comparing the effect of different mutations, we can begin to tease apart how these changes lead to HCM. It allows us to look closely at how and why the cells adapt to the mutation in that way, and to get data and relate it to the thickness of the heart wall and all the other things that happen downstream. 

Nearly fifteen years after the research began while Pruitt was still at Stanford and that led to this collaborative paper, CRISPR technology enables researchers to design cells expressing specific mutations that are linked to cardiac diseases, and then assess molecular and functional changes to determine the cellular impact of individual mutations that have been identified in patients with HCM. These studies will provide a mechanistic understanding of how individual mutations at the molecular level translate to HCM in patients. 

In this project, once the mutation was introduced, the cells were assayed in a collaboration between the Pruitt and Bernstein labs, using traction force microscopy, an assay that allows simultaneous observation of a beating cell and the force it generates. The Spudich led separate studies of the same mutated protein at the molecular level using an optical trap, in which light pressure is applied to control precisely the location and force of an actin “dumbbell” held between beads as myosin heads walk along the actin, to measure myosin’s power cycle. The assay revealed that the P710R mutation reduced the step size of the myosin motor (i.e. the length of each step) and the rate at which the myosin detaches from actin.
In a collaboration with University of Kentucky researcher Kenneth Campbell, these observations were then compared to a computational model of how the myosin motors interact in the cell to generate force. The results confirmed a key role for regulation of what is called myosin’s “super-relaxed state.” As Pruitt explains, “Myosin heads spend a lot of time in a super-relaxed state, referring to when it is unbound from actin. Any mutation or drug that shifts how long or how strongly myosin motors are bound to actin will change the cell force production and change downstream signaling events that drive remodeling and growth or hypertrophy.”

The P710R mutation in this study was found to destabilize the super-relaxed state. As a result, more myosin heads are bound to actin in cells that harbor the mutation, which explains the increase in force that was observed in those cells. 

For Pruitt, a key takeaway from the work, beyond the important scientific findings, is the value of sustained collaboration. “The scales that the paper covers are not typically the subject of research in any one lab or even any two labs,” she says. “That’s why the paper has so many authors, including several students and postdocs working with me, James Spudich, and Daniel Bernstein. 

“It’s significant scientifically but also satisfying in that this level of integration makes it possible to test this idea across multiple scales. It’s been fun to work across these labs and these skills on such an extensive, multidisciplinary collaboration, and to see that the power of molecular measurements and computation, and the cell-derived measurements that allow us to genetically engineer and dissect out a single mutation,” says Pruitt. “This is really phenomenal, to test directly how a particular mutation introduces changes that lead to HCM.”

As a result of this collaboration, Pruitt says, “We can understand what goes on at the cell level. Then we can start to develop models and identify next-generation drug therapies. Instead of just identifying the symptoms, we can look at the mechanisms that underlie the dysfunctions and then address those at the cell level before it turns into a disease.”

Featured image: Professor Beth Pruitt © UC Santa Barbara Engineering

Provided by UC SANTA BARBARA Engineering

Research Deepens Understanding of Rare Vaccine-Induced blood Clotting Condition (Medicine)

A national study involving UCL has deepened understanding of the symptoms, signs and outcomes of patients with a novel blood-clotting condition associated with the Oxford/AstraZeneca vaccine.

The rare condition, known as vaccine-induced immune thrombocytopenia and thrombosis (VITT), is characterised by a blockage of veins and a marked reduction of platelets, which are an important part of the blood clotting system. VITT was first identified in the UK by Professor Marie Scully (UCL Institute of Cardiovascular Science), also a Consultant Haematologist at UCLH, and Dr Will Lester from University Hospitals Birmingham NHS Foundation Trust.

The new research paper, published in the New England Journal of Medicine (NEJM), reports on the first 220 cases of definite and probable VITT in the UK.

The paper is based on cases of VITT presented by 182 consultant haematologists from 96 NHS Trusts, and builds on understanding about the condition outlined in an April 2021 NEJM paper led by Professor Scully which reported on 23 early cases of VITT.

Meanwhile, a study led by Dr Richard Perry (UCL Queen Square Institute of Neurology and UCLH) published in the Lancet earlier this month provided the most detailed observations so far of cases of cerebral venous thrombosis (CVT) caused by VITT. CVT is the commonest and severest manifestation of VITT.

In the latest paper, researchers found that the overall mortality rate of those presenting to hospitals with definite or probable VITT was 23%.

Almost all patients experienced the condition between five and 30 days after their first vaccination. There was no difference in incidence between the sexes, and no prior medical condition was seen more often than expected for the general population.

The chances of death increased significantly the lower the platelet count and the greater the activation of the blood clotting system, increasing to 73% in patients with a very low platelet count and intracranial haemorrhage following blood clots in the brain.

41% of patients had no previous medical diagnoses and 85% were less than 60 years old. Overall incidence in individuals under 50 was estimated to be 1 in 50,000 – consistent with reports from other countries.

Researchers said the optimal treatment was still uncertain, but that treatment approaches were being continually refined in real time. For instance, the introduction of the use of plasma exchange in the most severe cases has led to survival rates that were significantly better than would be predicted based on baseline characteristics.

In addition, the research provides further evidence that non-heparin-based blood thinners should be used to tackle blood clotting in cases of VITT, and that use of intravenous immunoglobin was associated with better outcomes.

Professor Scully said: “As a new condition we are still learning about how best to diagnose and manage VITT, but as time goes on, we have been able to refine our treatment approaches and improve rates of survival and chance of recovery. This continuous learning in real time has been made possible thanks to collaboration between colleagues across the UK.”

Dr Sue Pavord at Oxford University Hospitals (OUH) NHS Foundation Trust, lead author of the latest study, said: “We have worked relentlessly to understand and manage this new condition, so that the hugely successful vaccine roll out can continue, which is the most viable solution to the global pandemic.”


Blood clot. Credit: Anne Weston, Francis Crick Institute. CC BY-NC 4.0. Source: Wellcome Collection.

Link to paper:

Provided by UCL

Potential New Therapeutic Approach For Chronic Inflammatory Bowel Diseases (Medicine)

FAU research team identify messenger substance protecting cells in the intestine

Why people suffer from chronic inflammatory bowel diseases (IBD) such as ulcerative colitis is only partially understood. However, it is known that the bacteria of the intestinal flora and dysfunction in the immune system play an important role. In patients with IBD, an increased number of cells in the intestinal wall, known as epithelial cells, die. Bacteria then pass from the interior of the intestine into the damaged intestinal wall, causing inflammation and further cell death. The epithelial barrier, the barrier between the intestinal contents and the intestinal wall also becomes more permeable. With increasing cell death, the disease also progresses as more bacteria settle in the damaged intestinal wall – a vicious circle. A research team led by Prof. Dr. Christoph Becker from FAU has now found a mechanism that could prevent cell death, break the vicious circle and potentially be used as a therapy for inflammatory bowel diseases. The results have now been published in the renowned journal Nature Cell Biology.

In mice and tissues of ulcerative colitis patients, researchers found that a messenger substance called prostaglandin E2 can protect epithelial cells from a special form of cell death, necroptosis. Prostaglandins are hormone-like messenger substances that have various effects in the organism. Researchers have found that prostaglandins such as prostaglandin E2 are released in the body during inflammation. However, it is not yet fully understood how prostaglandins regulate inflammatory processes.

In recent years, the researchers have already shown that the incorrect regulation of necroptosis leads to cell death and thus to holes in the intestinal barrier. Prostaglandin E2 prevents this by binding to EP4 receptors on the epithelial cells. The more of these receptors are activated, the fewer cells die, according to the FAU team from the Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology – at Universitätsklinikum Erlangen. Patients with high levels of EP4 on the cell surface show a milder course of disease than patients with low levels of EP4.

The activation of the receptors by prostaglandin E2 thus counteracts the progression of intestinal inflammation. Together with colleagues in Canada, the research team tested an artificially produced molecule that can activate the EP4 receptor, like prostaglandin E2. Treatment with this molecule could prevent excessive cell death in the intestinal barrier and block bacteria from penetrating it. These findings offer a promising new therapy approach for ulcerative colitis and other chronic inflammatory bowel diseases.

Featured image: Microscopic image of a cultured intestinal epithelial cell with cell death programme activated (red). Pores form in the cell membrane (green) causing the cell to die. The nucleus is shown in blue. © FAU

Further information

Patankar, J.V., Müller, T.M., Kantham, S. et al. E-type prostanoid receptor 4 drives resolution of intestinal inflammation by blocking epithelial necroptosis. Nat Cell Biol 23, 796–807 (2021).

Provided by Friedrich-Alexander-Universität Erlangen-Nürnberg

World Exclusive: CAR-T Cell Therapy Successfully Used Against Autoimmune Disease (Medicine)

20-year-old patient with systemic lupus erythematosus treated with a new therapeutic approach for the first time worldwide

It all started with joint pain and a red facial rash: the then 16-year-old Thu-Thao V had already undergone several medical examinations in three cities when she was diagnosed with systemic lupus erythematosus (SLE) in February 2017 at Universitätsklinikum Erlangen. In the life-threatening autoimmune disease, which mainly affects young women, the immune system attacks its own cells in various organ systems.

After different immunosuppressive therapies failed to improve her symptoms, Thu-Thao V was treated with CAR-T cells by researchers from the German Centre for Immunotherapy (DZI) at Universitätsklinikum Erlangen in March 2021. Almost six months after the cell therapy, her joint pain has now disappeared and the 20-year-old has fully recovered. ‘I can even do normal sports again,’ says Thu-Thao V.

The findings were published in the New England Journal of Medicine.

The immune system usually distinguishes between foreign and endogenous cells, tolerating the body’s cells and attacking foreign cells to protect the organism, for example, from viruses and bacteria. ‘In SLE, parts of the immune system go crazy and form antibodies against their own genetic material, which inevitably leads to severe inflammatory reactions in the organs,’ explains Prof. Dr. med. univ. Georg Schett, Director of the Department of Medicine 3 – Rheumatology and Immunology, Universitätsklinikum Erlangen.

During the worst phase of the disease, student Thu-Thao V had to take almost 20 tablets every day so that her body could compensate for the stress of her misguided immune system. ‘The joint pain was also accompanied by water retention due to my renal insufficiency, strong palpitations and hair loss. After an acute episode, the symptoms were particularly severe,’ says Thu-Thao V.

Everything else had failed

‘We were standing with our backs to the wall,’ says Prof. Dr. Gerhard Krönke, senior physician at the department. All therapies aimed at suppressing the patient’s malfunctioning immune system failed. Even at this point, giving up was not an option for the treatment team and researchers decided to bring CAR-T cells into play.

‘CAR stands for chimeric antigen receptor which is an artificial receptor,’ explains Prof. Dr. Andreas Mackensen, Director of the Department of Medicine 5 – Haematology and Oncology. ‘Immune cells, or T cells, from the patient are genetically engineered in the laboratory to add the CAR. The CAR recognises special antigens on the surface of the target cells and destroys them. Cell therapy with CAR-T cells is already being successfully used to treat leukaemia and lymphoma.’

In the case of the young SLE patient, the CAR-T cells were programmed to render harmless the B cells that form antibodies against the body’s own cells.

Rapid improvement thanks to CAR-T cells

Thu-Thao V.
20-year-old Thu-Thao V is doing very well almost six months after CAR-T cell therapy, and the symptoms of SLE have vanished. (Image: Michael Rabenstein/Universitätsklinikum Erlangen)

In March 2021, Thu-Thao V was the world’s first patient treated with SLE CAR-T cells. ‘We were very surprised how quickly her condition improved immediately after the cell infusion,’ reports Prof. Dr. Dimitrios Mougiakakos, senior physician at the Department of Medicine 5. ‘The CAR-T cells have done their job excellently and quickly rendered the B cells causing the disease harmless. All the symptoms of SLE disappeared along with the antibodies that were attacking the body.’

Thu-Thao V was able to discontinue all immunosuppressive drugs including cortisone. She has now been completely free of symptoms for almost six months, so far there are no signs of a recurrence of the disease.

‘I can finally breathe properly and sleep through the night, and I no longer have any water retention, and the redness in my face has disappeared. My hair is also growing much more densely,’ says Thu-Thao V. Her heart function is also back to normal: her heart rate has dropped from an average of 115 to 130 beats per minute to 80 beats per minute.

‘We see this as a milestone in the therapy of autoimmune diseases,’ say the scientists. They are now planning a clinical study with CAR-T cells in patients with autoimmune diseases.

The study on CAR-T cell therapy was published in the New England Journal of Medicine and supported by the German Research Foundation (DFG) Collaborative Research Centres SFB1181 (Switching points for resolving inflammation) and SFB/TRR221 (Controlling graft-versus-host and graft-versus-leukaemia immune reactions after allogenic stem cell transplants)

Systemic lupus erythematosus (SLE)

Lupus erythematosus is a rare chronic inflammatory autoimmune disease that mainly affects young women of childbearing age. The disease is found throughout the world but it is also rare. It occurs in about 50 out of 100,000 people. Two main forms are distinguished: cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE). CLE only affects the skin with typical butterfly-shaped skin changes in body parts exposed to the sun, especially around the eyes. SLE also affects internal organs (e.g. kidney inflammation, joint pain, inflammation of the lungs and heart). In some cases, lupus can be fatal. The causes of the disease have not yet been fully identified. Experts assume a genetic predisposition in combination with UV light and hormonal influences.

Featured image: Prof. Dr. Andreas Mackensen (Director/Department of Medicine 5, l.) and Prof. Dr. med. univ. Georg Schett (Director/Department of Medicine 3, right) are pleased that the CAR-T cell therapy has worked so well for their patient Thu-Thao V. (Image: Michael Rabenstein/Universitätsklinikum Erlangen)

Provided by Friedrich-Alexander-Universität Erlangen-Nürnberg 

From Blood to Brain: Delivering Nucleic Acid Therapy To The CNS (Neuroscience)

Researchers from Tokyo Medical and Dental University (TMDU), Takeda Pharmaceutical Co., Ltd. and Ionis Pharmaceuticals, USA, show that heteroduplex oligonucleotide drugs conjugated with cholesterol cross the blood–brain barrier effectively with intravenous or subcutaneous dosing 

Watch video on YouTube: 

Antisense oligonucleotide (ASO) therapy has the potential to ameliorate many neurodegenerative diseases at the genetic level to suppress the production of harmful proteins or non-coding RNAs. Previously, achieving delivery of ASO with adequate concentrations in the central nervous system (CNS) with systemic dosing was difficult. Now, researchers from Japan and the USA have developed a drug delivery platform that overcomes this hurdle. 

Evolution has equipped the brain with protection against both mechanical and molecular injury. The blood–brain barrier (BBB) is a selectively semipermeable barricade of endothelial cells lining the capillaries; working with specific transporter proteins, it functions as a fastidious gatekeeper between the circulation and the CNS, barring foreign molecules, including drugs.

ASOs are pharmaceutical molecules that can target disease at the genetic level. They comprise a few dozen base pairs arranged in an ‘antisense’ or reverse order and prevent production of pathogenic proteins through binding to the ‘sense’ strand of mRNA targets. Single-stranded ASOs show great promise against CNS disorders such as spinal muscular atrophy. However, they do not enter the CNS effectively following systemic administration and require direct intrathecal injection. This may be hazardous particularly for patients with lumbar spinal deformity or on blood-thinners.

The research team had recently developed DNA/RNA heteroduplex oligonucleotide (HDO) technology capable of highly efficient RNA degradation in vivo. First author Tetsuya Nagata explains, “We found that cholesterol conjugated HDO (Chol-HDO), unlike cholesterol-ASO, efficiently reached the CNS following subcutaneous or intravenous administration in experimental animals. The Chol-HDO platform showed significant dose-dependent target gene reductions with prolonged action in all CNS regions and cell types.” 

Further, the researchers confirmed that this beneficial outcome was not at the expense of vascular barrier integrity. They also investigated the pharmacokinetics of multiple injections as well as subcutaneous dosing (which may be self-administered). Additionally, the effects were confirmed across species and against other neurogenerative disease gene targets such as myotonic dystrophy type 1, Alexander disease and amyotrophic lateral sclerosis.

“Systemic doses being higher, adverse effects such as mild decrease in platelets were expected,” says Nagata. “However, divided or subcutaneous dosing can rescue these. We may also strategize by initiating treatment with intrathecal dosing to rapidly achieve therapeutic concentrations, followed by intravenous or subcutaneous maintenance as needed.” 

“Our innovative therapeutic platform for blood-to-brain delivery of ASOs may revolutionize management of neurodegenerative diseases,” senior author Takanori Yokota claims. “Future research will help define the specific molecular pathways thus optimizing delivery of ASO pharmacotherapy to the CNS.”

The article, “Systemically administered DNA/RNA heteroduplex oligonucleotides achieve blood to brain delivery and efficient gene knockdown in the CNS” was published in Nature Biotechnology  at DOI:10.1038/s41587-021-00972-x

Featured image: (A) Drastic target gene (RNA) suppression in the cerebral cortex when Blood-brain-barrier heteroduplex oligonucleotide (BBB-HDO) administered intravenously to mice. (B) RNA images in the cerebral cortex after administration of BBB-HDO to mice. The brown signal indicates RNA, but the signal is almost completely suppressed by BBB-HDO. (Scale: 100 μm). (C) Live image of mouse brain observed by in vivo confocal laser microscopy. The single-stranded antisense oligonucleotide (ASO) remains in the blood vessels of the brain, while the BBB-HDO is directly transferred into the brain. © TMDU

Provided by Tokyo Medical and Dental University

Discovery of Origin of Oesophageal Cancer Cells Highlights Importance of Screening For Pre-cancerous Barrett’s Oesophagus (Biology)

Abnormal cells that go on develop into oesophageal cancer – cancer that affects the tube connecting the mouth and stomach – start life as cells of the stomach, according to scientists at the University of Cambridge.

The study, published today in Science, found that a particular subtype of oesophageal cancer known as oesophageal adenocarcinoma is always preceded by Barrett’s oesophagus – abnormal cells of the oesophagus – even if these cells are no longer visible at the time of cancer diagnosis. This confirms that screening for Barrett’s is an important approach to oesophageal cancer control.

The techniques we used have shown us the internal processes that happen in the stomach cells when they become Barrett’s. The big question now is: what triggers these genes?

Karol Nowicki-Osuch

Cancer of the oesophagus is the sixth most deadly cancer, and oesophageal adenocarcinoma is on the rise in western countries. Scientists and doctors have known for some time that the development of this cancer is linked with Barrett’s oesophagus, which shows up in endoscopy as a pink ‘patch’ in the surface of oesophagus and affects around one out of every 100 to 200 people in the United Kingdom – and between 3 and 13 people out of 100 with this condition will go on to develop oesophageal adenocarcinoma in their lifetime. However, the question of where these abnormal cells come from has been a mystery that has baffled scientists for decades.

A multidisciplinary group of scientists led by Professor Rebecca Fitzgerald at the Medical Research Council Cancer Unit, University of Cambridge, today provides the most comprehensive explanation to date.

Dr Lizhe Zhuang, joint first author of the study, said: “It’s intriguing that, although Barrett’s oesophagus predominately occurs in the lower part of oesophagus close to stomach, it has so-called ‘goblet cells’ resembling a much more distant organ, the small intestine. Over the past twenty years there have been at least six different hypotheses about the origin of Barrett’s oesophagus. Using the latest techniques, we believe we have arrived at an answer to this mystery.”

The research team analysed tissue samples from patients with Barrett’s oesophagus and from organ donors who have never had the condition. The samples were collected as part of the Cambridge Biorepository for Translational Medicine at Addenbrooke’s Hospital, part of Cambridge University Hospitals NHS Foundation Trust.

Lead authors Dr Karol Nowicki-Osuch and Dr Lizhe Zhuang established a detailed ‘atlas’ of human cells and tissues from all possible origins of Barrett’s oesophagus, including oesophageal submucosal glands, an elusive tissue structure that acts in a similar way to saliva glands and has never before been isolated from fresh human tissue.

The researchers then compared the maps of cells from healthy tissues, Barrett’s oesophagus and oesophageal adenocarcinoma using a number of state-of-the-art molecular technologies. These included single cell RNA sequencing, a powerful technology that enables researchers to investigate the functions of a large number of individual cells. They also looked at methylation profiles –chemical modifications to the DNA of cells in the tissue – and at genetic linage to trace back where a particular cell type originated.

The results showed a striking similarity between stomach cells and Barrett’s oesophagus, suggesting that the cells at the very top of the stomach can be reprogrammed to adopt a new tissue identity, becoming more like intestine cells, and replace the oesophageal cells. Furthermore, in this new study the team showed that two genes, MYC and HNF4A, are the keys that switch the tissue identity from stomach to intestinal cells.

Dr Karol Nowicki-Osuch, joint first author of the study, said: “The techniques we used have shown us the internal processes that happen in the stomach cells when they become Barrett’s. The big question now is: what triggers these genes? It’s likely to be a complex combination of factors that include bile acid reflux (often felt as heartburn) and other risk factors, such as obesity, age, male sex and Caucasian ethnicity.”

Importantly, the researchers found that all oesophageal adenocarcinoma cells begin as stomach cells before transforming into Barrett’s cells and then into cancer cells.

Professor Fitzgerald added: “Even if the pre-cancerous Barrett’s is not visible at the time of cancer diagnosis, our data suggests the cancer cells will have been through this stage. This has been debated for some time, but our conclusion is important as it means that screening for Barrett’s is an important approach to controlling oesophageal cancer.”

Michelle Mitchell, Chief Executive of Cancer Research UK, said, “Today’s insights into the origin of oesophageal adenocarcinoma could help inform future research efforts into how to diagnose this type of cancer early – which is key for improving patient outcomes.

“This research goes hand in hand with other recent successes in early detection such as Cytosponge, the sponge-on a-string test, which we funded to detect Barrett’s in patients with heartburn symptoms.”

Detecting cancer earlier will be a key focus of the Cambridge Cancer Research Hospital, a partnership between Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge to build a new specialist cancer hospital. The hospital will combine modern NHS clinical space with two new research institutes, including the National Institute for the Early Detection of Cancer, which will lead the way in helping advance early cancer detection techniques.

The research was largely funded by the Medical Research Council, Wellcome and Cancer Research UK.

Further information on oesophageal cancer and Barrett’s oesophagus is available via Cancer Research UK.

Nowicki-Osuch, K & Zhuang, L et al. Molecular phenotyping reveals the identity of Barrett’s esophagus and its malignant transition. Science; 13 Aug 2021; DOI: 10.1126/science.abd1449

Provided by University Of Cambridge

Researchers Identify New Enzyme That Infects Plants – Paving The Way For Potential Disease Prevention (Botany)

Scientists have identified an unusual enzyme that plays a major role in the infection of plants – and have shown that disabling this enzyme effectively stops plant disease in its tracks.

By discovering previously unexplored ways in which crop pathogens break through plant cell walls, the scientists have opened up opportunities for developing effective disease control technologies.

The new research, published in Science, describes a family of enzymes found in a microorganism called Phytophthora infestans. The enzymes enable crop pathogens to degrade pectin – a key component of plant cell walls – thereby enabling the pathogens to break through the plant’s defences to infect the plant.

Led by biologists and chemists from the University of York, the international team of researchers discovered the new class of enzymes that attack pectin called LPMOs. The team also showed that disabling the gene that encodes this enzyme rendered the pathogen incapable of infecting the host.


P. infestans is known to cause potato late blight, a devastating plant disease that led to widespread starvation in Europe and more than a million deaths in Ireland in the 1840s, in what became known as ‘The Great Famine’. Plant infection continues to cause billions of dollars’ worth of damage to global crop production each year and continues to threaten world food security. 

The identification of this new gene could open up new ways of protecting crops from this important group of pathogens.

Lead author on the report, Dr Federico Sabbadin, from the Biology Department’s Centre for Novel Agricultural Products (CNAP), at the University of York said: “These new enzymes appear to be important in all plant pathogenic oomycetes, and this discovery opens the way for potentially powerful strategies in crop protection”.

Professor Simon McQueen-Mason, also from CNAP, remarked that the work was “the result of interdisciplinary collaborations between biologists and chemists at York along with plant pathologists at the James Hutton Institute, and genomicists at CNRS, with invaluable molecular insights from Professor Neil Bruce (CNAP) and Professors Gideon Davies and Paul Walton in the Department of Chemistry at York.”

Featured image: Phytophthora infestans found in potato plants. © University of York

For more information:
Secreted pectin monooxygenase promotes plant infection by pathogenic oomycetes. Chemistry (2021). DOI: 10.1126 / science.abj1342

Provided by University Of York

Early Land Plants Evolved From Freshwater Algae, Fossils Reveal (Botany)

The world may need to start thinking differently about plants, according to a new report in the journal Science by researchers who took a fresh look at spore-like microfossils with characteristics that challenge our conventional understanding about the evolution of land plants.

Found in rock samples retrieved in Australia more than 60 years ago, the microfossils dating to the Lower Ordovician Period, approximately 480 million years ago, fill an approximately 25-million-year gap in knowledge by reconciling the molecular clock—or pace of evolution—with the fossil spore record—the physical evidence of early plant life gathered by scientists over the years.

This reconciliation supports an evolutionary-developmental model connecting plant origins to freshwater green algae, or charophyte algae, said Boston College paleobotanist Paul Strother, a co-author of the new report. The “evo-devo” model posits a more nuanced understanding of plant evolution over time, from simple cell division to initial embryonic stages, rather than large jumps from one species to another.

“We found a mix of fossils linking older, more problematic spore-like microfossils with younger spores that are clearly derived from land plants,” said Strother. “This helps to bring the fossil spore record into alignment with molecular clock dates if we consider the origin of land plants as a long-term process involving the evolution of embryonic development.”

The fossil record preserves direct evidence of the evolutionary assembly of the plant regulatory and developmental genome, Strother added. This process starts with the evolution of the plant spore and leads to the origin of plant tissues, organs, and eventually macroscopic, complete plants—perhaps somewhat akin to mosses living today.

“When we consider spores as an important component of the evolution of land plants, there is no longer a gap in the fossil record between molecular dating and fossil recovery,” Strother said. Absent that gap, “we have a much clearer picture of a whole new evolutionary step: from simple cellularity to complex multicellularity.”

As a result, researchers and the public may need to re-think how they view the origin of terrestrial plants—that pivotal advance of life from water to land, said Strother.

Early land plants evolved from freshwater algae, fossils reveal
A new assemblage of fossil spores of Lower Ordovician age, about 480 Ma, are intermediate in character between controversial Cambrian forms and well-accepted plant spores from later Ordovician and Silurian deposits. This linkage aligns fossil spores with molecular data and helps explain why megafossil plants axes don’t appear in the geological record until 75 million years later during the Silurian. Credit: Paul Strother

“We need to move away from thinking of the origin of land plants as a singularity in time, and instead integrate the fossil record into an evo-devo model of genome assembly across millions of years during the Paleozoic Era—specifically between the Cambrian and Devonian divisions within that era,” Strother said. “This requires serious re-interpretation of problematic fossils that have previously been interpreted as fungi, not plants.”

Strother and co-author Clinton Foster, of the Australian National University, set out tosimply describe an assemblage of spore-like microfossils from a deposit dating to the Early Ordovician age—approximately 480 million years ago. This material fills in a gap of approximately 25 million years in the fossil spore record, linking well-accepted younger plant spores to older more problematic forms, said Strother.

Strother and Foster examined populations of fossil spores extracted from a rock core drilled in 1958 in northern Western Australia. These microfossils are composed of highly resistant organic compounds in their cell walls that can structurally survive burial and lithification. They were studied at Boston College, and at the ANU’s Research School of Earth Sciences, with standard optical light microscopy.

“We use fossil spores extracted from rock drill cores to construct an evolutionary history of plants going back in time to the very origin of plants from their algal ancestors,” said Strother. “We have independent age control on these rock samples, so we study evolution by looking at changes in the kinds of spores that occur over time.”

Molecular biologists also look at evolutionary history through time by using genes from living plants to estimate the timing of plant origins using “molecular clocks”—a measurement of evolutionary divergence based on the average rate during which mutations accumulate in a species’ genome.

However, there are huge discrepancies, up to tens of millions of years, between direct fossil data and molecular clock dates, said Strother. In addition, there are similar time gaps between the oldest spores and when actual whole plants first occur.

These gaps resulted in hypotheses about a “missing fossil record” of the earliest land plants,” said Strother.

“Our work seeks to resolve some of these questions by integrating the fossil spore record into an evolutionary developmental model of plant origins from algal ancestors,” Strother said.

Featured image: A new assemblage of fossil spores of Lower Ordovician age, about 480 Ma, are intermediate in character between controversial Cambrian forms and well-accepted plant spores from later Ordovician and Silurian deposits. This linkage aligns fossil spores with molecular data and helps explain why megafossil plants axes don’t appear in the geological record until 75 million years later during the Silurian. Credit: Paul Strother

Reference: A fossil record of land plant origins from charophyte algae, Science  13 Aug 2021: Vol. 373, Issue 6556, pp. 792-796. DOI:

Provided by Boston College