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Category: Bases moléculaires et structurales du vivant

Inflammation and cancer: identifying the role of copper paves the way for new therapeutic applications

Posted on by Graziella Cara

équipe CurieThe research team developed a “drug prototype” capable of mitigating both the mechanisms of inflammation and the processes potentially involved in metastatic spread. © Institut Curie / BELONCLE Frank

For the first time, researchers from Institut Curie, the CNRS and Inserm have uncovered a previously unknown chain of biochemical reactions. This chain involves copper and leads to metabolic and epigenetic alterations[1] that activate inflammation and tumorigenesis. But there is more; the research team developed a “drug prototype” capable of mitigating both the mechanisms of inflammation and the processes potentially involved in metastatic spread. Published in the journal Nature on April 26, 2023, these results provide hope for new therapeutic opportunities to control inflammation and cancer.

Inflammation is a complex biological process that can eradicate pathogens and promotes repair of damaged tissues. However, deregulation of the immune system can lead to uncontrolled inflammation and produce lesions instead. Inflammation is also involved in cancer. The molecular mechanisms underlying inflammation are not fully understood, and so developing new drugs represents a significant challenge.

As far back as 2020, Dr. Raphaël Rodriguez, CNRS research director and head of the Chemical Biology team at Institut Curie (Equipe Labellisé Ligue Contre le Cancer) at the Cellular and Chemical Biology laboratory (Institut Curie/CNRS/Inserm), had shed new light on a membrane receptor called CD44, which marks immune responses, inflammation and cancer progression. Dr. Rodriquez and his team showed that CD44 helped import iron into cell[2], triggering a series of reactions leading to activation of genes involved in the metastatic process.

“This is a cell plasticity phenomenon we continued to study, investigating other metals potentially internalized by CD44, notably copper,” he explains.

 

Copper causing epigenetic alterations

Along with his colleagues[3], Dr. Rodriguez has now reached a new milestone.

The research team managed to identify a signaling pathway involving copper and leading to the expression of pro-inflammatory genes in macrophages, the cells present in all tissues and playing an important role in innate immunity.

Once internalized in macrophages, copper enters into the mitochondria (the organelle responsible for cell respiration and energy production), where it catalyzes the oxidation of NADH into NAD+  (nicotinamide adenine dinucleotide, a molecule needed for the activity of certain enzymes). The increase of NAD+ in cells enables the activity of certain enzymes involved in the production of metabolites essential for epigenetic regulation. These metabolites thus, contribute to the activation of genes involved in inflammation.

 

Inflammation and cancer: shared molecular mechanisms

The scientists did not stop there, they also designed molecules able to bind to copper, inspired from the structure of metformin.[4] By testing these new molecules on models of acute inflammation, they found that a synthetic dimer of metformin, LCC-12 (also termed Supformin), reduced activation of macrophages and attenuated inflammation.

“Our work has enabled us to develop a drug prototype that inactivates copper chemistry in the cell’s metabolic machinery, thus blocking expression of the genes involved in inflammation”, explains Dr. Rodriguez.

To finish, they applied this therapeutic strategy to cancer cell models engaged in an epithelial-mesenchymal transition[5]. Here again, Supformin blocked the cellular mechanism and thus the cell transformation.

“The genes activated in cancer cells are not the same as those expressed in immune cells, but the chain reaction leading to epigenetic alterations is identical”, explains Dr. Rodriguez.

These results thus reveal the role of copper in cancer cells and their ability to adopt a metastatic nature.

Dr. Raphaël Rodriguez concludes: “Our study reveals that the inflammatory and cancer processes depend on similar molecular mechanisms and could therefore in the future benefit from similar innovative therapies, such as those tested with Supformin.”

The explanations of Dr. Raphaël Rodriguez in video :

 

[1]Epigenetics is the study of the mechanisms at play in gene regulation, which is essential to the action of cells and to maintaining their identity. Unlike genetic mutations, which are permanent, epigenetic modifications on DNA or histones are reversible.

[2] Read the press release “Cancer: a new mechanism that regulates cell activity involving iron”: https://curie.fr/sites/default/files/medias/documents/2020-08/CPCNRS-CD44ferCancer-FR-emb.pdf

[3] This study was conducted at Institut Curie, in the Cellular and Chemical Biology unit (Institut Curie, CNRS, Inserm), in collaboration with UVSQ, Raymond Poincaré hospital (AP-HP), Gustave Roussy hospital, the Institut de chimie moléculaire et des matériaux d’Orsay (CNRS/University Paris-Saclay), the Multimodal Imaging Center (CNRS/Institut Curie/Inserm/University Paris-Saclay), the Center for Infection and Immunity of Lille (CNRS/Inserm/Institut Pasteur de Lille/CHU of Lille/University of Lille), Institute of Pharmacology and Structural Biology (CNRS/University of Toulouse III) along with British and Australian researchers.

[4]Metformin is a treatment used for Type-2 diabetes, and is able to form a bimolecular complex with copper.

[5] Epithelial-mesenchymal transition is the first step in enabling cancer cells to metastasize.

Extreme Temperatures During Pregnancy: A Possible Impact on the Lung Development of Newborn Girls

Posted on by Graziella Cara

Grossesse

Exposure to extreme temperatures from the fetal stage could impact health. © Fotalia

Exposure to extreme temperatures from the fetal stage could impact health. This is what suggests a study by researchers from Inserm, Université Grenoble Alpes and CNRS, based on the SEPAGES cohort[1], intended to study the impact of various environmental factors on the health of pregnant women and their children. In this research, to be published in JAMA Network open, associations were found in newborn girls, between in utero exposure to very high or very low ambient temperatures from the second trimester of pregnancy and the alteration of several respiratory parameters.

The thermoregulation implemented by the body in response to variations of temperature requires the adaptation of maternal blood flow and cardiac function which, when this occurs during pregnancy, can be to the detriment of the fetus. Physiological alterations have also been observed in animals in response to heat stress exposures, such as impaired placental development with reduced blood flow, or oxidative stress which, outside of normal conditions, may affect the health of mother and child. External temperature could therefore have an impact on embryo-fetal development.

A team led by Inserm researchers Johanna Lepeule and Ariane Guilbert at the Institute for Advanced Biosciences (Inserm/Université Grenoble Alpes/CNRS), wished to verify this hypothesis using data from the SEPAGES cohort (Assessment of Air Pollution Exposure During Pregnancy and Effect on Health). Made up of pregnant women and children from their pregnancies, this cohort makes it possible to study the effect of various environmental factors on health.

 

Exposure Modeled Throughout Pregnancy

The researchers modeled the exposure to ambient temperatures of 343 women and their children, from conception to their first weeks of life. At the same time, they evaluated the respiratory function of the newborns at around 6 to 7 weeks after birth. Various measurements were used to calculate the tidal volume (volume of air that enters and leaves with each breath), respiratory rate (number of breaths per minute), and functional residual capacity (FRC) (volume of air remaining in the lungs after an expiration)[2].

Since fetal development and respiratory function differ slightly according to sex, the research team also compared outcomes between girls and boys.

 

Associations That Vary According to Sex

In boys, the scientists did not observe any significant alterations in lung function associated with external temperature during pregnancy. However, they found that girls exposed in utero from the second trimester of pregnancy to the highest or lowest temperatures had a lower FRC and a higher respiratory rate than those exposed to temperatures closer to the average.

In addition, girls exposed to very low temperatures in utero had decreased tidal volume.

“Although the observed variations are not pathological in nature and do not make it possible to predict a future respiratory disorder, explains Lepeule, the various lung function measurements all converge towards an association between in utero exposure to high or low temperatures and poorer lung performance in newborn girls. “

New analyses of the respiratory data collected in children at 3 and 8 years of age will be needed in order to determine whether these associations persist over the long term or whether they are reversible over time.

In the meantime, “these findings underpin the importance of developing public policies to protect pregnant women and their children from extreme temperatures, particularly in the current context of climate change,” concludes Lepeule.

 

[1] The SEPAGES couple-child cohort (Assessment of Air Pollution Exposure During Pregnancy and Effect on Health), coordinated by Inserm and Université Grenoble Alpes, aims to characterize the exposure of pregnant women and their children to environmental contaminants and study their effect on the health of pregnant women, fetuses, and children.

[2] This residual volume plays an essential role in the maintenance of lung function: as the lungs are elastic, they retract during the muscle relaxation that enables expiration. At the end of expiration, the residual volume makes it possible to limit the retraction forces placed on the lungs so that the pulmonary territories remain open to gas exchange (O2 and CO2 essentially). Otherwise, the lungs would close on themselves, and the alveoli would collapse, meaning that gas exchange could no longer take place.

A “Nano-Robot” Built Entirely from DNA to Explore Cell Processes

Posted on by Léa Surugue

Scientists have designed a “nano-robot” made up of three DNA origami structures. © Gaëtan Bellot/Inserm

Constructing a tiny robot from DNA and using it to study cell processes invisible to the naked eye… You would be forgiven for thinking it is science fiction, but it is in fact the subject of serious research by scientists from Inserm, CNRS and Université de Montpellier at the Structural Biology Center in Montpellier[1]. This highly innovative “nano-robot” should enable closer study of the mechanical forces applied at microscopic levels, which are crucial for many biological and pathological processes. It is described in a new study published in Nature Communications.

Our cells are subject to mechanical forces exerted on a microscopic scale, triggering biological signals essential to many cell processes involved in the normal functioning of our body or in the development of diseases.

For example, the feeling of touch is partly conditional on the application of mechanical forces on specific cell receptors (the discovery of which was this year rewarded by the Nobel Prize in Physiology or Medicine).

In addition to touch, these receptors that are sensitive to mechanical forces (known as mechanoreceptors) enable the regulation of other key biological processes such as blood vessel constriction, pain perception, breathing or even the detection of sound waves in the ear, etc.

The dysfunction of this cellular mechanosensitivity is involved in many diseases – for example, cancer: cancer cells migrate within the body by sounding and constantly adapting to the mechanical properties of their microenvironment. Such adaptation is only possible because specific forces are detected by mechanoreceptors that transmit the information to the cell cytoskeleton.

At present, our knowledge of these molecular mechanisms involved in cell mechanosensitivity is still very limited. Several technologies are already available to apply controlled forces and study these mechanisms, but they have a number of limitations. In particular, they are very costly and do not allow us to study several cell receptors at a time, which makes their use very time-consuming if we want to collect a lot of data.

DNA origami structures

In order to propose an alternative, the research team led by Inserm researcher Gaëtan Bellot at the Structural Biology Center (Inserm/CNRS/Université de Montpellier) decided to use the DNA origami method. This enables the self-assembly of 3D nanostructures in a pre-defined form using the DNA molecule as construction material. Over the last ten years, the technique has allowed major advances in the field of nanotechnology.

This enabled the researchers to design a “nano-robot” composed of three DNA origami structures. Of nanometric size, it is therefore compatible with the size of a human cell. It makes it possible for the first time to apply and control a force with a resolution of 1 piconewton, namely one trillionth of a Newton – with 1 Newton corresponding to the force of a finger clicking on a pen. This is the first time that a human-made, self-assembled DNA-based object can apply force with this accuracy.

 

The team began by coupling the robot with a molecule that recognizes a mechanoreceptor. This made it possible to direct the robot to some of our cells and specifically apply forces to targeted mechanoreceptors localized on the surface of the cells in order to activate them.

Such a tool is very valuable for basic research, as it could be used to better understand the molecular mechanisms involved in cell mechanosensitivity and discover new cell receptors sensitive to mechanical forces. Thanks to the robot, the scientists will also be able to study more precisely at what moment, when applying force, key signaling pathways for many biological and pathological processes are activated at cell level.

“The design of a robot enabling the in vitro and in vivo application of piconewton forces meets a growing demand in the scientific community and represents a major technological advance. However, the biocompatibility of the robot can be considered both an advantage for in vivo applications but may also represent a weakness with sensitivity to enzymes that can degrade DNA. So our next step will be to study how we can modify the surface of the robot so that it is less sensitive to the action of enzymes. We will also try to find other modes of activation of our robot using, for example, a magnetic field,” emphasizes Bellot.

 

[1] Also contributed to this research: the Institute of Functional Genomics (CNRS/Inserm/Université de Montpellier), the Max Mousseron Biomolecules Institute (CNRS/Université de Montpellier/ENSCM), the Paul Pascal Research Center (CNRS/Université de Bordeaux) and the Physiology and Experimental Medicine: Heart-Muscles laboratory (CNRS/Inserm/Université de Montpellier).

A Gene Therapy Studied in Steinert’s Disease

Posted on by Léa Surugue

Steinert’s disease is caused by the abnormal repetitions of a small DNA sequence in the DMPK gene. ©Unsplash

Myotonic dystrophy type 1 (DM1) or Steinert’s disease is a rare and debilitating genetic neuromuscular disease affecting multiple organs and with a fatal outcome. No treatment is available at present. Encouraged by previous research into its molecular causes, researchers from Inserm, CNRS, Sorbonne Université, Lille University Hospital and Université de Lille, in partnership with the Institute of Myology, at the Center for Research in Myology and the Lille Neuroscience & Cognition center, have developed and tested a promising gene therapy that acts directly at the origin of the disease. Initial findings published in Nature Biomedical Engineering show correction of molecular and physiological alterations in mouse skeletal muscle1.

Myotonic dystrophy type 1 (DM1), otherwise known as Steinert’s disease, is a rare, hereditary and genetic neuromuscular condition affecting around 1 in 8,000 people. Debilitating and fatal, it is referred to as a “multisystem” condition because it simultaneously affects the muscles (muscle weakening and atrophy called “dystrophy”; muscle relaxation impairment called “myotonia”) and other organs (cardiorespiratory, digestive and nervous systems, etc.). The expression and course of the disease vary from one patient to the next and no treatment exists as yet.

It is caused by the abnormal repetition of a small DNA sequence (triplet CTG2) in the DMPK (DM1 Protein Kinase) gene located on chromosome 19. In healthy individuals, this sequence is present but repeated between 5 and 37 times. However, in patients with DM1, a mutation occurs whereby the number of triplets increases, producing up to several thousand repetitions.

About the mechanisms enabling gene expression

To obtain the production of a protein, a gene (located in the cell nucleus) is first transcribed into a molecule of RNA. To become a messenger RNA (mRNA), it undergoes maturation, particularly involving splicing. This basically means that the molecule is cut into pieces, some of which are eliminated and others attached. Thanks to this finely regulated process, one gene can lead to the synthesis of different mRNA and therefore of different proteins. After splicing, the mature mRNA will eventually be translated into protein, outside of the cell nucleus.

In Steinert’s disease, the mutated gene is transcribed but the mutant mRNA are retained in the cell nuclei as characteristic aggregates. In the cells of people with DM1, the MBNL1 proteins that normally bind to certain RNA in order to regulate their splicing and maturation are “captured” by the RNA that carry the mutation.

Thus sequestered in the aggregates, it is impossible for them to perform their functions, resulting in the production of proteins that function less well or not at all, some of which have been linked to clinical symptoms.

The team led by CNRS Research Director Denis Furling at the Myology Research Center (Inserm/Sorbonne Université/Institute of Myology) in association with that of Nicolas Sergeant, Inserm Research Director at the Lille Neuroscience & Cognition Centre (Inserm/Université de Lille/Lille University Hospital), focused on a therapeutic strategy to restore the initial activity of MBNL1 in skeletal muscle cells expressing the mutation responsible for Steinert’s disease.

To do this, the scientists engineered modified proteins that present, like the protein MBNL1, binding affinities for the RNA carrying the mutation and as a consequence act as a decoy for these RNA.

When expressing these decoy proteins in vitro in muscle cells from patients with DM1, they observed that they were captured by the mutated RNA instead of the MBNL1 proteins. The latter were then released from the aggregates of mutated RNA and regained their normal function. As a result, the splicing errors initially present in these cells disappeared. Finally, the mutated RNA bound to the decoy proteins proved to be less stable and could be more easily and effectively eliminated by the cell.

Aggregates of mutant DMPK-RNA containing pathological triplet (red) repetitions visualized by FISH-immunofluorescence in the nuclei (blue) of muscle cells (green) isolated from patients with Myotonic dystrophy type1 © Denis Furling and Nicolas Sergeant

The research team then transposed this technique into an animal model in order to verify the validity of this approach in vivo. With the help of viral vectors used in gene therapy, the decoy proteins were expressed in the skeletal muscle of mouse models of Steinert’s disease. In these mice, a single injection was effective, over a long period of time and with few side effects, in correcting the muscle damage associated with the disease, particularly the splicing errors, myopathy and myotonia.

“Our findings highlight the efficacy on Steinert’s disease symptoms of a gene therapy based on the bioengineering of RNA-binding decoy proteins with strong affinity for the pathological repetitions present in the mutated RNA, in order to release the MBNL1 proteins and restore their regulatory functions,” declares Furling. However, the authors point out that additional studies are needed before this therapy can be transposed into a clinical study. “This research paves the way for the development of therapeutic solutions in the context of other diseases in which pathological RNA repetitions cause splicing regulation dysfunction,” concludes Sergeant.

 

1 The striated skeletal muscle is the muscle that is attached to the skeleton by tendons and which, due to its ability to contract, enables the performance of precise movements in a well-defined direction.

2 The coding sequence of a gene consists of the chaining of different combinations of four nucleic acids: adenine, guanine, cytosine, and thymine (replaced by uracil in RNA). These are organized in triplets (or codons) whose correct “reading” by the cell machinery enables the expression of a protein.

Human “Jumping Genes” Caught in the Act!

Posted on by Graziella Cara

©Photo AdobeStock

Over the course of evolution, the genomes of most living organisms have grown more complex thanks to transposable elements, a.k.a. “jumping genes,” or DNA fragments that can move and copy themselves from one chromosome location to another. Researchers from Inserm, the CNRS, Université Côte d’Azur, and Université de Montpellier were able to capture these “jumping genes” just after they moved. The researchers compared their observations with existing databases. Their work, to be published in Molecular Cell, shows that the integration of “jumping genes” in humans is not random. Instead, it is thought to be influenced by specific genome properties. These results open up new perspectives for interpreting whole genome sequencing data.

Transposable elements, also known as “jumping genes,” are small DNA fragments that can multiply and move in the chromosomes of most living organisms. They have proliferated so intensely in mammals and primates that they make up more than half of our chromosomes! Of course, they don’t jump all at once in all of our cells. Of all the copies present in our DNA, only a small fraction remain active. All the rest are molecular remnants reflecting millions of years of evolution, during which harmful insertions were eliminated and beneficial ones retained.

In humans, the most active jumping genes are L1 retrotransposons. They can alter or destroy genes when they jump, triggering the manifestation of genetic diseases like hemophilia and muscular dystrophy. L1 retrotransposons are also particularly active in some forms of cancer, and could be involved in cellular aging or in some mental illnesses.

Do L1 retrotransposons target specific chromosome regions, or do they choose their positions at random? Teams led by Inserm head researchers Gaël Cristofari and Simona Saccani working at the Nice Institute for Research on Cancer and Aging (IRCAN, Inserm, CNRS, Université Côte d’Azur), along with their colleagues at Université de Montpellier, were able to use a “high-speed” genome sequencing technique to catch actively jumping genes right after they jumped to a new position.

After comparing their observations with genomic and epigenomic databanks, the researchers were able to identify which genome characteristics influenced the integration of the L1 retrotransposons. The most notable characteristic was DNA replication, and natural selection phenomena after integration played a preponderant role.

“We already knew that L1 retrotransposons tend to accumulate in specific areas of our chromosomes, especially heterochromatin. But we didn’t know whether that reflected a particular attraction to those regions, or if they are simply tolerated in those regions and eliminated elsewhere through natural selection. When we know where they jump to and which copies are retained over the course of evolution, we can discover – by deduction – the regions where they can do damage,” explains Cristofari.

Their results make it easier to understand how jumping genes can trigger mutations in humans, and how they contribute to the evolution of our genetic heritage. In the future, this research could be used to interpret whole genome sequencing data, particularly in personalized medicine and vast sequencing programs.

The research was made possible with financial support from the Fondation pour la Recherche Médicale, Cancéropôle PACA, the European Research Council, the French National Research Agency, the Labex Signalife, the Groupement de Recherche sur les Eléments Transposables (CNRS, GDR 3546), the FHU OncoAge, and the European Erasmus Mundus Mobility with Asia program.
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