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The 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.

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.

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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

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