The presence of a compound present in cruciferous vegetables, indole-3-carbinol, is essential to make certain cancer treatments effective. © Photo by Monika Borys /Unsplash

It is a universally recognized truth that vegetables are good for your health. A study conducted by Institut Curie and Inserm reveals that the presence of a compound present in cruciferous vegetables, indole-3-carbinol, is essential to make certain cancer treatments effective. The researchers also highlight the biological mechanisms at play and explain how the absence of indole-3-carbinol induces dysfunction at the level of cytotoxic T lymphocytes and decreases the effectiveness of immunotherapy. Illustrating the importance of understanding the relationships between nutrition and immunity, these results are published in Nature Communications on December 2, 2025.

“We now know that the response to cancer treatments can be influenced by many environmental factors, such as nutrition. In particular, it has been shown that the composition of the intestinal microbiota, itself modulated by our diet, plays a role in the effectiveness of certain immunotherapy treatments (by anti-PD1 immune checkpoint inhibitor). And it is precisely this link between nutrition and anti-cancer treatments that we wanted to explore, ” explains Dr. Elodie Segura, Inserm Research Director at Institut Curie (Immunity and Cancer unit).

The role of indole-3-carbinol in the effectiveness of anti-PD1 treatments

In a study conducted at Institut Curie, the group of Dr. Elodie Segura, Inserm Research Director, was interested in one nutrient in particular: indole-3-carbinol, a molecule present in large quantities in cruciferous vegetables (cabbage, broccoli, cauliflower, watercress, turnips, arugula, radishes, etc.). In order to evaluate their role, the researchers compared the effectiveness of an immunotherapy in animals that had received two different diets: one containing indole-3-carbinol and the other one – without it. With indole-3-carbinol, the anticancer treatment has proven to be effective in 50 to 60% of animals. On the other hand, when indole-3-carbinol is eliminated, the effectiveness of the treatment decreases to 20%.

“These results show us that when we remove this compound present in cabbages, there is a drastic decrease in the effectiveness of anti-PD1 immunotherapy,“ summarizes Dr. Elodie Segura.

Cytotoxic T lymphocytes, pivot of the mechanism

It is known that cancer cells are capable of inactivating the cells of the immune system, thus preventing the cancer from being attacked by cytotoxic or “killer” cells. However, immunotherapy treatments, by anti-PD1 immune checkpoint inhibitor, counteract the inhibition by cancer of cytotoxic T cells and allows them to reactivate. Thanks to this treatment, the cytotoxic T lymphocytes that are reactivated become able to recognize the tumor cells and destroy them.

The researchers managed to identify the mechanisms of action of indole-3-carbinol at play in immunotherapy. They have thus demonstrated that indole-3-carbinol binds to a transcription factor called Aryl Hydrocarbon Receptor (AhR), in particular expressed in cytotoxic T lymphocytes[i].

In the absence of indole-3-carbinol, cytotoxic T lymphocytes are unable to respond to treatment.

“Normally, during an anti-PD1 immunotherapy, the lymphocytes are stimulated and reactivated to detect tumor cells. However, in the absence of indole-3-carbinol in the diet, the lymphocytes are not able to recover their functions,” continues to explain Elodie Segura. “Our work makes it possible to better understand the role of nutrients in anti-tumor immune responses. For patients, these data could make it possible to optimize diets in order to ensure the effectiveness of treatments.”

While waiting for these results to be confirmed through dedicated clinical studies, cancer patients are encouraged to follow nutritional recommendations and their doctor’s advice.

[i] Cytotoxic T lymphocytes, also called CD8+ T lymphocytes, are a category of immune cells intended to kill target cells, such as cells infected by viruses, or tumor cells.

© Unsplash

In ICARUS-BREAST 01 study, more than half of the patients with metastatic breast cancer saw their disease reduce or disappear completely thanks to the treatment. In some cases, this response has now lasted for more than two years. Dr Barbara Pistilli, Head of the Breast Cancer Group at Gustave Roussy and Guillaume Montagnac, Inserm researcher, Head of Tumor Cell Dynamics unit, coordinated the study, the results of which have just been published in Nature Medicine. They highlight the efficacy of patritumab deruxtecan (HER3-DXd), an antibody HER3-directed-drug conjugate (ADC), in patients with hormone receptor-positive metastatic breast cancer who had already received multiple treatments, including hormone therapy, chemotherapy, and targeted therapies. The study also offers early insights into why some patients respond better to this targeted therapy than others. This research was conducted within the UNLOCK program at the IHU Prism, in collaboration with Daiichi Sankyo.

Breast cancer remains the most common malignant tumour among women, with 2.3 million new cases and 685,000 deaths worldwide in 2020[1]. These figures underline the urgent need to develop new treatments in this indication.

Antibody-drug conjugates (ADCs) are an emerging class of therapeutics that combine an antibody, designed to recognise and bind to cancer cells, with a cytotoxic agent, often a chemotherapy drug. The antibody delivers its toxic payload directly into the cancer cell while sparing as much healthy tissue as possible.

ADCs have already shown highly encouraging clinical results in a number of solid and haematological tumours. However, despite their promise, their efficacy remains variable across patients. To date, the biological mechanisms underlying this variability, especially the causes of resistance, are still poorly understood. Identifying predictive biomarkers of response is a key challenge in optimising the personalised use of these therapies.

Published in Nature Medicine, ICARUS-BREAST 01 is a phase II trial sponsored by Gustave Roussy. It evaluated the efficacy and safety of patritumab deruxtecan (HER3-DXd) in 99 patients with HR+/HER2- metastatic breast cancer whose disease had progressed following treatment with a CDK4/6 inhibitor and one line of chemotherapy. The trial also included an exploratory component aimed at identifying biomarkers predictive of response or resistance to this innovative therapy.

Promising Clinical Results

Patritumab deruxtecan is an ADC designed to target the HER3 protein, which is expressed in a high proportion of hormone receptor-positive breast cancer cells. This protein is known to play a role in resistance mechanisms to certain standard treatments, including hormone therapy and some targeted therapies.

From May 2021 to June 2023, ninety-nine women received patritumab deruxtecan by infusion every three weeks, until disease progression or the onset of a serious toxicity. The study met its primary endpoint: 53.5%of patients experienced a significant reduction in tumour size with patritumab deruxtecan, and around 63% of patients derived clinical benefit from the treatment (tumour shrinkage or disease stabilisation lasting at least six months). Notably, two patients experienced complete disappearance of visible signs of disease, a response that has now lasted more than two years.

The median follow-up period was 15.3 months. Median progression-free survival was 9.2 months, and the average duration of response was 9.3 months. The most common adverse events were fatigue (83%), nausea (75%) and diarrhoea (53%). The safety profile was consistent with that previously reported.

The Role of the UNLOCK Programme

The exploratory research component of ICARUS-BREAST 01 shed light on why some patients respond better than others do to patritumab deruxtecan, by identifying biomarkers linked to resistance mechanisms. This research, conducted within Gustave Roussy’s UNLOCK programme at the IHU Prism, was based on exploratory analysis of tumour samples taken before and after treatment, as well as imaging and genetic data.

These exploratory analyses suggest that the response to the drug may be linked to how HER3 is distributed within the tumour and to the absence of certain mutations, such as ESR1. Another finding indicates that disease control may last longer in patients whose tumours express higher levels of HER3.

Samples collected during treatment revealed that the drug’s efficacy appears to depend on its ability to penetrate the tumour, and on the activation of a specific immune response marked by an interferon signature, proteins naturally produced by the body that play a key role in stimulating the immune system.

“In this study, HER3-DXd demonstrated promising efficacy and good tolerability in patients with advanced hormone receptor-positive breast cancer who had exhausted standard treatment options,” says Dr Pistilli. She adds, “ICARUS-BREAST 01 also highlights interesting biological insights that could ultimately help us better identify patients who are most likely to benefit from this approach. These initial results now need to be confirmed by larger trials, some of which are already under way internationally and will soon open in France. Another study, ICARUS-BREAST 02, is currently ongoing with HER3-DXd. It aims to evaluate the efficacy of this ADC in combination with Olaparib following progression on a previous ADC, trastuzumab deruxtecan (T-DXd).”

[1]Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA: A Cancer Journal for Clinicians 2024;74(1):12–49

© Fotalia

A new class of molecules capable of killing the cancer cells that are refractory to standard treatments and responsible for recurrence has just been developed by scientists at Institut Curie, the CNRS, and Inserm. This crucial advance in the fight against metastatic cancer is based on identifying the cellular site for ferroptosis initiation, a natural process, catalysed by iron, that sparks the oxidative degradation of cell membranes. These promising preclinical results will be published in the journal Nature on 7 May 2025.

Current anticancer treatments essentially target the primary tumour cells that proliferate quickly, but do not effectively eliminate specific cancer cells able to adapt to existing treatments and which exhibit high metastatic potential¹. Yet metastases are responsible for 70% of cancer deaths.

A French research team from Institut Curie, the CNRS and Inserm has just developed a new class of small molecules that bring about the destruction of cell membranes,and hence triggers cell death. Led by scientists at the Laboratory of Biomedicine (Institut Curie/CNRS/Inserm)², this study is based on the remarkable properties of what are known as drug-tolerant persister cancer cells, with high metastatic potential. The latter express a large quantity of the protein CD44 at their surface, allowing them to internalise more iron, making them more aggressive and able to adapt to standard treatments. These cells are consequently more sensitive to ferroptosis, a cell death process catalysed by iron, which causes oxidation and the degradation of membrane lipids.

Thanks to innovative chemistry developed by the team led by Raphaël Rodriguez, researchers showed that the cell death initiated by iron in lysosomes3 can alter the structure of intracellular membrane compartments. In the lysosomal compartment, iron can react with hydrogen peroxide, generating oxygen-centred radicals, highly-reactive chemical entities that damage cell membranes. This reaction then propagates in the cell forming lipid peroxides in the membranes of other cellular organelles, ultimately causing cell death. Ferroptosis thus results from the cell’s failure to repair the membrane damage.

Using these initial discoveries, the scientists successfully conceived and synthesised a new class of small molecules that can activate ferroptosis: phospholipid degraders. The molecules possess one fragment that allows them to target the cell membrane (plasma membrane)—and to then accumulate in lysosomes via endocytosis—as well as another part that binds to and increases the reactivity of iron, which is abundant in this compartment of pro-metastatic cancer cells, thereby triggering ferroptosis. The molecule fentomycin (Fento-1) was designed to be fluorescent, allowing scientists to visualise it in the cell using high-resolution microscopy, as well as to confirm its localisation in lysosomes.

After the administration of Fento-1, the researchers observed a significant reduction in tumor growth in pre-clinical models for metastatic breast cancer, in addition to a pronounced cytotoxic effect on biopsies of pancreatic cancer and sarcoma patients, thereby confirming the treatment’s effectiveness at the pre-clinical level⁴ for these cancers, for which the effectiveness of standard chemotherapy is limited.

Clinical tests are needed to show that this ability to induce ferroptosis could serve as a therapeutic avenue that complements current chemotherapy in the fight against cancer, especially by targeting cancer cells that are pro-metastatic and refractory to standard treatments.

Ferroptosis diagram. Iron is internalized in the cell via the protein CD44 present on its surface, allowing it to acquire metastatic properties and tolerance to standard treatments through epigenetic reprogramming, which plays a key role in cell adaptation. The activation of lysosomal iron by a phospholipid degrader causes the oxidation and rupture of cell membranes, leading to cell death.

1 – Tumour cells that detach from their site of origin and migrate toward other parts of the body, forming new tumours known as metastases. This ability to spread is a characteristic of advanced cancers.

2 – This research primarily involved scientists from the Laboratory of Biomedicine (Institut Curie/CNRS/Inserm/PSL Research University), the Cancer Research Center of Marseille (Aix-Marseille Université/CNRS/Inserm/Institut Paoli Calmette), the APHP (Hôpital Paul-Brousse), the Institute of Molecular Chemistry and Materials of Orsay (CNRS/Université Paris-Saclay), Harvard T.H. Chan School of Public Health, Helmholtz Zentrum München, Julius-Maximilians-Universität Würzburg,, Columbia University and the University of Ottawa.

3 – Lysosomes are the organelles responsible for the degradation of cell debris, biological macromolecules, foreign particles (bacteria, viruses, and parasites), and damaged intracellular organelles.

4 – Pre-clinical tests on animals showed a significant decrease in tumour volume after the lymphatic injection of Fento-1, with tolerance to treatment.

This research notably received support from the Ligue contre le cancer (3 Equipe Labellisées), the Horizon 2020 Research and Innovation Programme of the European Union (ERC), the Fondation pour la recherche médicale, the Fondation Charles Defforey–Institut de France, the Klaus Grohe Foundation, l’Institut national du cancer, the Ile-de-France Region, the ANR, the Fondation Bettencourt Schueller, the CNRS, Institut Curie, and Inserm.

Around 30% of cancers develop in the wake of chronic localised inflammation. This is particularly the case of certain colorectal cancers, or cancers of the small intestine, liver or pancreas. © Adobe Stock

Nearly one in three cancers develops following chronic inflammation, whose origin remains unclear. In a new study, researchers from Inserm, CNRS, Université Claude-Bernard Lyon 1 and the Léon Bérard Centre at the Cancer Research Center of Lyon[1]identified lymphocytes involved in the inflammatory processes and that are thought to be implicated in the generation of these cancers. This research opens up new avenues in terms of prevention and treatment, and its findings have been published in Nature Immunology.

Around 30% of cancers develop in the wake of chronic localised inflammation. This is particularly the case of certain colorectal cancers, or cancers of the small intestine, liver or pancreas. However, many questions remained unanswered regarding their development. Is one specific immune cell responsible for the inflammatory process that leads to cancers, or more than one? And if so, which?

Answering these questions is one of the objectives of Inserm Research Director Julien Marie[2] and his team at the Cancer Research Center of Lyon (Inserm/CNRS/Université Claude-Bernard Lyon 1/Léon Bérard Centre) in order to better understand how the disease is initiated.

The researchers were particularly interested in TH17 lymphocytes – a population of immune cells which are already known to be involved in many inflammatory diseases, such as multiple sclerosis and Crohn’s disease.

Cells that cause cancer

The hypothesis was that TH17 cells are not a homogeneous population, but can actually be divided into several subgroups. Using single-cell RNA sequencing approaches, the scientists demonstrated this heterogeneity of TH17 cells within the gut.

‘More specifically, this study shows for the first time that there are actually eight TH17 subtypes with distinct roles. One of them has a tumorigenic role, which means that when certain activation barriers are removed, it will contribute to the development of cancers. On contact with these TH17 cells, the previously healthy gut cells become cancerous’, explains Marie.

The scientists then showed this tumorigenic population to be increased in patients at high risk of cancer. Finally, they also identified that a protein – cytokine TGF–β – is capable of inhibiting the formation of tumorigenic TH17 cells.

‘This study may make clinicians stop and think about the long-term use of immunotherapies in cancer patients, whose aim is to stimulate lymphocytes’, emphasises Marie.

While these therapies have transformed cancer care, they are also known to cause chronic gut inflammation. Therefore it is important to consider, for a given patient, the risks of immunotherapy being accompanied by the emergence of tumorigenic TH17 lymphocytes, which could eventually lead to the development of another cancer. Furthermore, this study lays the foundations for the development of new cancer preventive therapies by blocking the appearance of the TH17 subtype implicated by the scientists in this research.

[1]Scientists from the Institute of Molecular Genetics of Montpellier (CNRS/Université de Montpellier) also participated in this research.

[2]Julien Marie is the winner of the Bettencourt Coups d’Élan Prize for French Research.
Created by the Bettencourt-Schueller Foundation in 2000, this prize had been awarded to 78 French laboratories and over 900 researchers until 2021.

Cancer cell made in 3d software © Fotalia

Acute myeloid leukaemia is one of the deadliest cancers. Leukaemic stem cells responsible for the disease are highly resistant to treatment. A team from the University of Geneva (UNIGE), University Hospital of Geneva (HUG), and Inserm has made a breakthrough by identifying some of the genetic and energetic characteristics of these stem cells. Notably, a specific iron utilisation process. This process could be blocked, leading to the death or weakening of these stem cells without affecting healthy cells. These results, published in Science Translational Medicine, pave the way for new therapeutic strategies.

Acute myeloid leukaemia (AML) is the most common blood and bone marrow cancer in adults. Caused by an increase in immature cells that rapidly destroy and replace healthy blood cells (red and white blood cells and platelets), it is lethal in half of those affected under the age of 60, and in 85% of those over that age.

This unfavorable prognosis may be due to the presence of so-called ”dormant” or ”quiescent” leukaemic stem cells (LSCs), which evade chemotherapy. Often invisible, these cells can ”wake up” and reactivate the disease after an apparently successful course of treatment. Developing therapies that target these cells directly is therefore a major research challenge. However, the mechanisms controlling them are poorly understood.

By identifying genetic and metabolic characteristics specific to LSCs, a team from the UNIGE, HUG, and Inserm is providing new insights, as well as ways of combating the disease. These results, published in Science Translational Medicine, pave the way for a new therapeutic target and its clinical application.

A distinctive genetic signature

”Using advanced bioinformatics techniques, and in collaboration with the team of Dr Petros Tsantoulis from the Department of Oncology and Precision Oncology at the HUG, we first established that these quiescent cells contain a unique genetic signature consisting of 35 genes. When we used this signature in large clinical databases of patients with AML, we were able to show that this signature was strongly linked to the prognosis of the disease,” explains Jérôme Tamburini, associate professor in the Department of Medicine and the Centre for Translational Research in Onco-haematology (CRTOH) in the UNIGE Faculty of Medicine and at the Swiss Cancer Center Léman (SCCL), staff physician in the Division of Oncology at HUG, who led this research.

 

Locking a specific nutrient

The study also highlights a metabolic difference between dormant and active leukaemic stem cells. In general, to survive, cells trigger chemical reactions that enable them to break down nutrients and thus produce energy. This also involves ”autophagy”, a process that allows cells to recycle cellular components to generate new ones and to provide energy in case of a lack of external nutrients. Scientists have discovered that dormant leukaemic stem cells depend on ”ferritinophagy”, a specific form of autophagy targeting ferritin, the main iron storage molecule.

‘‘This process is mediated by a protein called NCOA4. It controls the availability of iron in cells. By inhibiting it, either genetically or chemically, we observed that leukaemia cells, especially dormant stem cells, are more likely to die, whereas healthy blood stem cells remain intact,” reveals Inserm researcher Clément Larrue, a former post-doctoral researcher in Jérôme Tamburini’s group, currently a post-doctoral researcher at the Toulouse Cancer Research Center, and first author of the study.

 

Towards clinical trials

Experiments conducted with mouse models have confirmed that blocking the NCOA4 protein reduces tumour growth, viability and self-renewal of leukaemic stem cells. Targeting ferritinophagy through this inhibition pathway could therefore be a promising therapeutic strategy. The compound used to block NCOA4 is in the early stages of development for future clinical trials, under the direction of one of the study’s co-authors, Jun Xu, a professor at Sun Yat-Sen University in China.

The next step for the UNIGE team will be to further explore further the mechanisms of ferritinophagy and its association with mitophagy, another key mechanism in the regulation of LSCs. This new stage of research is supported by the Swiss Cancer League.

A French-Swiss team has highlighted the long-term impact of socioeconomic inequalities on the quality of life of women who have had breast cancer. © Photo Angiola Harry / Unsplash

When it comes to health, inequalities can be seen at every level for women with breast cancer: prevention, screening, diagnosis, treatment, and survival. But what about their quality of life? A team from the University of Geneva (UNIGE), the University Hospitals of Geneva (HUG), Inserm, and Gustave Roussy has tracked nearly 6,000 women diagnosed with breast cancer over a 2-year period, showing that socioeconomic status has a major and lasting impact on their quality of life, despite identical medical treatment. These results from the UNICANCER-sponsored CANTO study, published in the Journal of Clinical Oncology, call for socioeconomic factors to be taken into greater account in support programmes for women with breast cancer.

Social and economic determinants (such as income and educational levels) impact how individuals cope with illness and are one of the main causes of inequalities in health. In cancer care, socioeconomic inequalities are present throughout the continuum of care, from prevention to diagnosis, treatment, and survival.

‘‘However, the extent of socioeconomic inequalities in the quality of life of women diagnosed with breast cancer and how these change during treatment was not known,’’ explains José Sandoval, an oncologist at the HUG Department of Oncology and a researcher in the Departments of Medicine and Community Health and Medicine at the UNIGE Faculty of Medicine, first author of this study. ‘‘We sought to quantify the inequalities in quality of life for these women, both at the time of diagnosis and in the following two years.’’

Nearly 6,000 women monitored over two years

The 5,900 women who took part in this study were treated in France for early breast cancer, a common form of cancer from which more than 80% of women recover.

‘‘Many of the women received heavy treatment in the first year following their diagnosis – including surgery followed by chemotherapy— followed by endocrine therapy in the second year. We followed them over two years to capture changes in quality of life over the medium term,’’ explains Gwenn Menvielle, research director at Inserm and at Gustave Roussy, who led this research.

The research team examined five areas of quality of life — general tiredness, psychological state, sexual health, and side effects — according to a number of socioeconomic indicators: level of education, household income, and perceived financial situation. Combining these elements produces a score where 0 indicates no inequalities.

Inequalities are increasing rapidly

At diagnosis, the inequalities in quality of life between the two socioeconomic extremes are notable, with a score of 6,7. The score increases to 11 during treatment, then remains at 10 two years after diagnosis, a higher score than at that time.

‘‘If we expected a certain degree of inequality at the start of the disease, the fact that these inequalities increase rapidly and persist for so long is a surprise,’’ mentions José Sandoval. ‘‘The impact on quality of life is much more pronounced for women with fewer resources, irrespective of the biological characteristics of their cancer, their age or the treatment they have received.’’

Why? The answers are to be found not in the treatment, which is similar for all women, but probably in all the elements of support around medical management.

‘‘Having the time, money, and access to information to take care of oneself, find support resources, and better manage the physical and psychological side-effects of the disease will probably be easier for women of high socioeconomic status than for, say, a single mother on a low income with no carer for her children,’’ points out José Sandoval. ‘‘These factors influence the disease and its consequences on patients’ physical and psychological health.’’

Taking better account of inequalities

Equal access to healthcare is not synonymous with the absence of inequality. The socioeconomic context can have a major impact on health status in the same way as biological characteristics.

‘‘When we talk about precision oncology, we need to consider the whole person, including their social dimension,’’ add the authors. ‘‘Our data concerns women treated in France, a country with equal healthcare access. In countries without a universal healthcare system, these inequalities are likely to be even more pronounced.’’

These results are part of the CANTO study: ‘‘étude des toxicités chroniques des traitements anticancéreux chez les malades porteurs de cancer localisé’’, supported by the French Government under the “Investment for the Future” program managed by the National Research Agency (ANR), grant n° ANR-10-COHO-0004.

Scanning electron microscopy. Here we see how platelets (in blue/purple) attach to two tumour cells (in red) in a pre-clinical mouse model. © Maria Jesus Garcia Leon (unit 1109 Inserm/Université de Strasbourg)

What if our blood platelets[1], which play a major role in maintaining the integrity of our circulatory system, were not always on our side? Research teams from Inserm, Université de Strasbourg and the French Blood Establishment have studied their role in the process of metastasis formation. Their findings suggest that platelets, by binding specifically to circulating cancer cells, promote their survival not just in the bloodstream, but also within metastases. This research, published in Nature Communications, also shows that using treatments to target this binding could fight the formation of metastases without the same bleeding risk[2] as with conventional antiplatelets.

A metastasis is a ‘secondary’ tumour which is usually formed from cancer cells that have broken off from a ‘primary’ tumour before migrating through the blood or lymphatic vessels to settle elsewhere in the body. During their migration, these cancer cells encounter the blood platelets – which prove to be unexpected allies. By binding to the cancer cells, the platelets help them to survive the immune cells in the blood environment and exit the bloodstream to reach their metastasis site.

However, not all cancer cells receive the same protection because some bind to the platelets more easily than others. This dictates their capacity to survive in the blood circulation, target certain vascular regions and, as such, their ability to metastasise. Furthermore, in-depth analyses of lung metastases have shown the presence of large numbers of platelets which may play a role that differs from or complements the role they play in blood vessels.

Two teams led by Inserm researchers Jacky Goetz, from the Molecular Immuno-Rheumatology Unit (Inserm/Université de Strasbourg) and Pierre Mangin, from the Biology and Pharmacology of Blood Platelets: Haemostasis, Thrombosis, Transfusion Unit (Inserm/French Blood Establishment/Université de Strasbourg), studied the moments at which the platelets intervened during the migration of cancer cells to promote their survival and spread. They also looked at how to counter this alliance without using conventional antiplatelet drugs which, by altering bleeding cessation, present the risk of haemorrhage.

In a mouse model, the researchers artificially induced controlled falls in the number of platelets at different stages in the formation of lung metastases. They saw that by removing platelets early (while they were still circulating in the blood), they limited the exit from the blood vessel of the cancer cells with a high affinity for the platelets, and thereby inhibited the formation of metastases. Those cancer cells with low levels of platelet binding were also affected, but only when the platelet level was decreased later, when the lung metastases were already formed.

‘These observations suggest that as well as protecting the cancer cells in the bloodstream, the platelets could also protect them against the immune system later on – i.e. within the metastases themselves, helping them to proliferate there, explains Goetz. So the aim of our future research will be to understand how the platelets colonise growing metastases.’

But how can we circumvent the issue of bleeding risk associated with antiplatelet treatments?

One initial avenue could involve a specific protein found on the platelet surface: glycoprotein VI (GPVI). Previous research has suggested that it could modulate the pro-metastatic activity of platelets without causing bleeding. The expression of this protein could be inhibited by glenzocimab, a molecule currently being evaluated in patients for the treatment of stroke. When they used glenzocimab in their animal model, the scientists saw that it effectively reduced the development of already established lung metastases, without affecting the cessation of bleeding.

‘These observations reinforce the idea of the contribution of platelets to the formation of metastases after cancer cells leave the circulation, explains Mangin. In addition, our research highlights the possibilities of developing new therapeutic strategies which, unlike conventional antiplatelet treatments, would not disrupt bleeding cessation and could therefore be considered in oncology, particularly to reduce the progression of lung metastases. Our two teams are currently working to explore this potential,’ adds the researcher.

This study, carried out on experimental animal models, reconciles previous contradictory data on the role of platelets in the metastatic process.

‘Studies in humans, for example on cohorts of patients with long-term exposure to antiplatelet agents for cardiovascular indications, or to evaluate the efficacy of oncology treatments in patients on antiplatelet therapy, could be excellent indicators for verifying these findings,’ concludes Goetz.

[1]Platelets (thrombocytes) present in the blood are not cells per se, but fragments of large bone marrow cells: megakaryocytes. They play a major role in the rapid cessation of bleeding (haemostasis). As such, platelet counts that are too low can lead to clotting disorders and therefore a risk of bleeding (in the event of injury, for example).

[2] See footnote 1

Neural organoid with immune environment magnified twice on the left, 20 times on the right: green macrophages, red and blue neural progenitor cells (fluorescence microscopy). © Gustave Roussy

French, Singaporean and British researchers, led by Prof. Florent Ginhoux, head of a research team at Gustave Roussy/Inserm, have succeeded in demonstrating in a neuronal organoid the role of the brain’s immune environment in its formation and development. The development of these three-dimensional structures integrating neuronal cells and the immune environment is, to date, one of the most complete in vitro models of the human brain. This work is published in Nature.

At Gustave Roussy, these organoids are used to model the development of childhood brain cancers, to understand their mechanisms and discover new avenues of treatment.

“Although microglial cells, immune cells derived from the evolution (differentiation) of primitive macrophages present in the embryonic brain, are known to contribute to multiple aspects of brain development and function, their precise role remains poorly understood and little studied”, says Prof. Florent Ginhoux, director of a research team at Gustave Roussy/Inserm and Senior Principal Investigatorat A*STAR’s Singapore Immunology Network (SIgN).

The use of neuronal organoids to study their functions is one of the avenues currently favored by research.

An organoid is a 3D structure grown in the laboratory which reproduces certain morphological and functional characteristics of a human body organ or tissue. In research, these cell-cultured pseudo-organisms are a new biological model in full development in various fields, notably neurology; most studies of neuron formation (neurogenesis) are based on animal models.

With their 3D structure, the function and properties of these organoids are close to those of a real organ, but not quite as advanced. They measure just one millimeter and have no thoughts, consciousness or emotions. By generating neural organoids from human induced pluripotent stem cells (iPS cells), it is possible to model some of the key features of early human brain development. “However, current approaches do not include microglial cells,“ explains Prof. Florent Ginhoux.

The international team of researchers led by Prof. Florent Ginhoux has succeeded in producing a new type of model: neuronal organoids with microglia, by cultivating together organoids and primitive-type macrophages, all generated from the same culture of iPS induced stem cells.

Organoids and primitive macrophages are prepared separately. It takes around 25 days to obtain them. The macrophages are then placed in contact with the organoids for a further 15 to 20 days.

In the model developed by the researchers, macrophages colonized the organoids. In this 3D environment, in contact with immature neuronal cells, they differentiated into microglial cells expressing the genes and functions specific to this cell type. These microglial cells proved capable of controlling the differentiation of neuronal precursors (so-called neuronal progenitor cells), thus limiting their multiplication (proliferation), while promoting synapse creation (synaptogenesis) and axon growth (axonogenesis), two key elements in the transmission of the nerve message from neuron to neuron.

A discovery within a discovery

Prof. Florent Ginhoux’s team also observed that the organoids’ microglial cells contain high levels of perilipin-2, a molecule belonging to a family of proteins that coat lipids – including cholesterol – in droplets, enabling them to be stored in and exported from the cells. Armed with these perilipin-2-laden droplets, microglial cells facilitate cholesterol transport to the organoids. The neural progenitor cells that absorb this cholesterol undergo metabolic reprogramming as they differentiate into nerve cells.

The approach developed by Prof. Florent Ginhoux and his colleagues has significantly advanced the complexification of organoid models by integrating microglial cells. This progress is illustrated by the discovery of a key lipid-mediated pathway between microglia and neural progenitor cells, essential for the synthesis of new neurons.

“With microglia cells incorporated, the neural organoids we have succeeded in generating are a new, more complete 3D model, closer to reality. We know that the immune system plays a fundamental role in the development of cancers, so at Gustave Roussy we’re going to use them to better understand and discover the mechanisms that regulate the development of pediatric brain tumors“, concludes Prof. Florent Ginhoux.

This work has been supported by the Gustave Roussy Foundation’s “Curing childhood cancer in the 21st century” campaign.

By studying immune cells in the lung, researchers from Institut Curie and Inserm have provided new knowledge on the topic.© Fotolia

Cancer and aging are closely linked processes, but the mechanisms underlying this relationship are still not well understood. By studying immune cells in the lung, researchers from Institut Curie and Inserm have provided new knowledge on the topic. They show that targeting ruptures of the nuclear envelope of these cells would represent a new opportunity for therapeutic intervention in age-related diseases, in particular cancer, thus improving the quality of life of the elderly in the long term. Funded by the Fondation ARC, this work has just been published in the journal Nature Aging.

Age is one of the main risk factors for the development of a number of diseases, such as viral or bacterial infections and neuro-degenerative diseases, but also cancers. The economic and societal issues related to the overall aging of the population constitute a major challenge. Furthermore, the notion of “healthy aging” increasingly suggests that targeting aging rather than its consequences is a far better strategy for reducing morbidity among the elderly.

More than two thirds of new cancers diagnosed in France occur in people over the age of 65[1]. The appearance of cancers with age can be explained by the accumulation of genetic alterations during a lifetime, less effective DNA repair mechanisms, and also by an aging immune system with diminished protective functions (immunosenescence). What are the mechanisms that govern this phenomenon? How can we develop strategies to counter immunosenescence?

The nucleus of immune cells sensitive to deformations

It is these questions that the Inserm and Institut Curie researchers attempted to answer. With time, DNA becomes fragile and one of the characteristic markers of cell aging is genome instability. When they patrol through the various tissues within the body, the immune system cells are sensitive to deformations which weaken their nucleus and promote DNA breakage. To maintain the structure of the nucleus and thus the genome’s integrity, the cell relies on a dense network of proteins, which include lamins. Among them lamin A/C is studied in particular since it undergoes alterations over the course of aging. In addition, mutations in the gene coding for this protein are known to cause early aging syndromes.

“Repeated ruptures of the nuclear envelope lead to DNA damage. It is vital to understand the processes at work in this regard since they promote not just aging of the body, but also the development of cancers. For example, ruptures of the nucleus make the DNA “visible” by damaging proteins, thus triggering a response from the cell that will promote the development of metastases“, explains Dr. Nicolas Manel, Inserm research director and team leader at Institut Curie.

 

“Two-photon” microscopy of the extreme deformation of an alveolar macrophage, when it passes between two alveoli. During these migrations the nucleus is also deformed, and it is at this point that the DNA can be damaged.

A protein identified in the lung: lamin A/C

At Institut Curie, the Innate Immunity team of Dr. Nicolas Manel, Inserm research director, studied a new experimental model in which the immune system’s cells are deficient in lamin A/C. Researchers looked closely at a population of lung macrophages – alveolar macrophages – which are highly dependent on lamin A/C for their survival. The role of these alveolar macrophages is to constantly monitor the lungs, and they are one of the main entry points for a number of pathogens.

The researchers showed that without lamin A/C, the alveolar macrophages show serious signs of fractures in their nucleus and damage to the DNA, leading to a dramatic drop in their number in the lungs. Furthermore, the surviving alveolar macrophages have many characteristics similar to those of aged alveolar macrophages, and accumulate markers characteristic of aging.

The team also revealed that without lamin A/C in the macrophages, the implantation and growth of lung tumors is a lot faster, encouraged by the malfunction of the aged macrophages.

The loss of lamin A/C would therefore constitute a mechanism for alveolar macrophage aging and a prime study model for understanding how lung cancers develop in the elderly.

“Our results open up many new opportunities for studying aging of the immune system, caused by rupture of the nuclear envelope and the decrease in its effectiveness against infections and tumors, in the lungs but also in other organs“, concludes Dr. Nicolas Manel.

These studies are funded in the amount of 2.5 million euros as part of the call for projects “Cancer and Aging” of Fondation ARC for cancer research.

[1] Source INCa : https://www.e-cancer.fr/Professionnels-de-sante/L-organisation-de-l-offre-de-soins/Oncogeriatrie/Epidemiologie