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Intestinal homeostasis and active cell migration

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Active cell migration would appear to play a crucial role in homeostatic renewal in the adult intestinal epithelium according to the findings to come out of a new study published in Science and conducted by Denis Krndija, a researcher in Danijela Matic Vignjevic’s team at the Research Center. These findings open up new possibilities in regulating this complex homeostatic process, and disruption triggered by cancer.

Drawing on a combination of biophysical modelling and 3D quantitative tissue imaging, as well as physical and genetic manipulations in mice, Denis Krndija and his co-authors from the cell invasion and migration team overseen by Danijela Matic-Vignjevic at the Research Center and in collaboration with Edouard Hannezo (Institute of Science and Technology, Austria) uncovered the existence of a migratory force active during homeostatic* epithelial renewal, in findings published in the Science journal. “This active migratory force is dependent on actin cytoskeleton dynamics induced by the Arp2/3 protein complex, a key factor in actin nucleation”, explains post-doctoral researcher Denis Krndija. The team analyzed cellular speed and tissue tension and density along the intestinal villi in order to quantitatively determine the equilibrium of both mitotic and active migratory forces in epithelial homeostasis. They demonstrated that mitotic pressure has a limited, short-range effect, restricted to the lower areas of the intestinal villi, where cells migrate more slowly. In the rest of the villi, however, cells migrate actively, using cellular protrusions.

However, according to CNRS team leader Danijela Matic-Vignjevic (UMR144 CNRS/Institut Curie cellular biology and cancer), “if this complex homeostatic process isn’t properly controlled, it can lead to high probability of failure, therefore resulting in pathologies such as tumors and inflammatory diseases”. The translational impact of this research was further explored by Dr. Marnix Jansen (University College London, United Kingdom) in the same issue of Science, offering up new prospects in research into colorectal cancer.

Over and above the key role it plays in absorbing nutrients, the intestinal epithelium serves as a barrier against bacterial, biochemical and mechanical attacks in its lumen’s harsh environment. The small intestine’s epithelium comprises a single layer of cylindrical cells that cover the intestinal villi, projections that protrude out into the intestine’s lumen, as well as crypts, small invaginations in the underlying connective tissue containing stem cells.

Cell migration at the heart of intestinal homeostasis

All epitheliums are continuously self-renewing, powered by mitotic stem cell division. According to Denis Krndija, “the intestinal epithelium is the body’s fastest self-renewing epithelium – we get a brand-new epithelium every week!”. The cycle starts via cell division in the crypts, after which the cells migrate upwards along the villi. Cell migration is therefore a key process in epithelial renewal. It had previously been thought to be a passive process, induced by the force generated by cell division in the crypts.

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Active cell migration is critical for steady-state epithelial turnover in the gut 

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Fevrier 26 - Mars 4, 2020

NON-CODING GENOME

Institut Curie
Organizer (s)

Sven Diederichs (Albert-Ludwigs-University Freiburg,  DE)

Antonin Morillon (Institut Curie, FR)

Marina Pinskaya (Institut Curie – Sorbonne Université, FR)

 

Scientific committee:

Déborah Bourc’his (Institut Curie, FR)

Maiwen Caudron-Herger (German Cancer Research Center DKFZ, Heidelberg, DE)

Ines Drinnenberg (Institut Curie, FR)

Arturo Londoño (Institut Curie, FR)

Alena Shkumatava (Institut Curie, FR)

Maxime Wery (Institut Curie, FR)

This course will explore the versatility of non-genic DNA elements and non-coding RNAs across a spectrum of cellular processes, in humans and model organisms, and their implication in physiology and disease. Internationally recognized experts will present their latest findings related to the identification and functional characterization of the non-coding genome and discuss novel concepts in genome regulation and evolution, with a strong emphasis on experimental and computational tools. Thematic sessions will include long and small non-coding RNAs, transposable elements, structural DNA repeats and non-coding regulatory elements. This course will offer to young students and research fellows the opportunity to broaden their knowledge and discuss their work with an international scientific community in a warm and stimulating environment at the Institut Curie in Paris.

 

Application deadline: December 1, 2019

Please, register here!

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Identifying two genes involved in regulating stem cells

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Adult stem cells, present in many tissues and organs, are difficult to identify and study in vivo. But studying them remains crucial for understanding the origin of cancers. In fact they have the capacity to divide and differentiate, including in cancer cells, thus helping the tumor to proliferate. The work of Louis Gervais, researcher at Institut Curie, brings new light to this area.

Understanding the mechanisms that regulate stem cells and their renewal and differentiation properties is now a major challenge in biomedical research. In recent years, stem cells have been the subject of many studies given their application in regenerative medicine, as tools for repairing or replacing defective organs. Adult stem cells are thus proposed as a primary possible source for the origin of cancers, meaning that studying them is even more vital. However, although adult, pluripotent stem cells are present in many tissues and organs (skin, intestine, muscles, brain), they remain rare and difficult to identify since they are hidden in a complex cellular environment which makes them difficult to study in vivo. The recent identification of adult intestinal stem cells in fruit flies offers new prospects for studying adult stem cells in vivo.

The epigenetic regulation of stem cells against tumor proliferation

Increasing numbers of research projects show the importance of epigenetic regulation of stem cells during development, and also in adults. A large proportion of epigenetic processes rely on dynamic modifications of chromatin (DNA or histones), which thus modulate gene expression. The research recently published in the journal Developmental Cell (Gervais et al., 2019) addresses this issue, showing in vivo how the epigenetic regulation of intestinal stem cells is vital in preventing proliferation of tumors.

Kismet and Trr: two key players in this regulation

Thanks to genetic screening, Louis Gervais, a researcher in Allison Bardin’s team (U934/UMR3215, genetics and developmental biology) and his colleagues, showed that chromatin regulators, Kismet/CHD7 and Trr/MLL3-4, are essential in maintaining the balance between proliferation and differentiation of intestinal stem cells. These genes are retained in mammals and frequently muted in cancers. They show that Kismet and Trr are strongly co-located on the entire genome, and that they jointly regulate a number of genes in intestinal stem cells. They take part in repressing the EGFR pathway by activating the expression of a pathway repressor: Cbl. These results have led us to propose that Trr and Kismet play a part in establishing the state of organization of chromatin needed to maintain a base level of proliferation of stem cells, thus limiting their anarchic expansion.

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Stem Cell Proliferation Is Kept in Check by the Chromatin Regulators Kismet/CHD7/CHD8 and Trr/MLL3/4

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Pedro Hernández, new junior team leader

Pedro-Hernandez

Pedro Hernández has set up a new research team within the Genetics and Developmental Biology Unit (Inserm U934/CNRS UMR 3215) headed up by Pierre Léopold. His established competence in developmental biology, immunolgy and physiology using the zebrafish model adds much-needed expertise on the integrative biology aspects set up within this Research Center unit.

That back-to-school feeling is in the air, and particularly for Pedro Hernández, who arrives at Institut Curie this September. Having completed his studies in his home country, this young researcher from Chile kickstarted his career in Freiburg (Germany) before joining the Institut Pasteur in Paris in 2015 as a post-doctoral researcher.

Throughout his career to date, in addition to his experience with the mouse model, he has amassed expertise in using another invaluable model for the life sciences scientific community: the zebrafish. This species’ transparent embryos are extremely easy to observe and are used as a model for understanding how complex physiological mechanisms work in humans. Pedro Hernández aims to uncover the principles governing how mucous membranes remain intact through the processes of intestinal repair, inflammation and development. As he explains, “disruption to intestinal mucosa repair linked to inflammation significantly increases the risk of cancer”.

The Development of Mucosal Immunity and Tissue Integrity team is currently being assembled and is based at the Research Center’s Paris site. The director of the Genetics and Developmental Biology Unit (Inserm U934/CNRS UMR 3215) Pierre Léopold is looking forward to working with the new team: “Pedro Hernández was selected by an international jury, and was one of 70 candidates […] His appointment arrives after a highly successful post-doctoral experience in Philippe Herbomel’s laboratory at the Institut Pasteur”. His plans feature “a very promising combination of physiology, immunology and developmental genetics”. The junior team leader brings highly complementary expertise in the research unit’s specialist subjects: Development, genetics and cancer.

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Immune cells ‘guided’ by our microbiota

Recherche dans le laboratoire de Sebastian Amigorena, porteur du projet Centre d’immunothérapie de l’Institut Curie, dans le cadre du projet d’établissement 2015-2020.

Intestinal microbiota is thought to control the development of some lymphocytes in the thymus, according to research conducted by Olivier Lantz, head of the CD4 lymphocytes, innate T cells and cancer team at Institut Curie’s Research Center, and François Legoux, one of the team’s researchers. A new piece of the puzzle in understanding the immune system, which may prove crucial in treating inflammatory digestive disorders and colon cancer.

In a study published in Science, François Legoux and Olivier Lantz, from l’Equipe lymphocytes CD4+, lymphocytes T innés et cancer (U932 Immunité et cancer / Institut Curie ) showed that some T cells, recognizing a bacterial product known as 5-OP-RU, need intestinal bacteria in order to develop in the thymus. Their work shows that some of the intestine’s bacteria secretes 5-OP-RU, which then travels through the body to the thymus, where it is trapped and presented to immature T cells. In response, the T cells that recognize the 5-OP-RU mature, increase in number and leave the thymus for the mucous membranes, and the intestine in particular. T cell ‘training’ in the thymus is therefore governed by microbiota molecules, a fact that challenges everything we thought we knew, and suggests that microbiota is an integral part of the immune self.

Critical issues

In the intestine, the T cells that recognize 5-OP-RU strengthen the epithelial barrier, thus encouraging healthy coexistence with microbiota. Understanding the interactions between our immune system and our microbiota is key, because their malfunctioning is linked to a number of illnesses and disorders. The T cells reinforce intestinal flora by restricting damage caused by bacteria – even symbiotic damage”, explains François Legoux. “Inflammation and disorders (such as Crohn’s disease, colitis, inflammatory bowel diseases, obesity and diabetes) linked to disruption in this symbiosis can occur. These T cells that have been trained by microbiota play an important role in all these disorders. There’s still a lot of work to be done in this area, but the crucial point is gaining a better understanding of how this symbiosis operates”.

This research’s findings seem highly promising. Working with this symbiosis could ultimately improve treatment for colon cancer and inflammatory digestive diseases, and help increase our understanding of how diabetes and obesity occur.

The human body contains around 39,000 billion bacteria, and major research efforts have been made in an attempt to better understand this symbiotic coexistence. In particular, the way in which the organism’s bacterial flora interacts with our defense system, the immune system, remains poorly understood. T cells play a key role in the immune system. They are produced in the thymus (hence the ‘T’), where they are trained to recognize and fight off foreign bodies in our organism over the course of our lifetimes. During their ‘training’, T cells likely to attack the body’s cells are eliminated, thus preventing autoimmune diseases. The thymus is therefore seen as the place where the immune system distinguishes between the self and the non-self.

 

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Antonin Morillon, winner of the ERC “Proof of concept” scholarship

Portrait Antonin Morillon

Antonin Morillon, Director of the Dynamic Genetic Information Unit, has just been awarded the ERC “Proof of concept” grant, a funding from the European Research Council. This prestigious grant will help him continue with his well-advanced research aimed to improve the early detection of prostate cancer without unnecessary biopsy.

Understanding prostate cancer
Prostate cancer is a deadly disease that affects about 400,000 men and that is the cause of 92,000 deaths a year in Europe. This type of cancer is intimately linked to aging. It develops slowly, from a normal cell that divides abnormally and proliferates uncontrollably. A mass of malignant cells, the tumor, forms and grows little by little. Tumor cells can reach nearby tissues and spread through the blood or lymphatic circulation. They spread to other parts of the body, such as lymph nodes near the prostate, bones or, later, more distant organs, such as the liver. They can later form metastases there. This whole process takes several years.

Complicated, multi-step screening
Prostate cancer screening is done by measuring the blood level of PSA (prostate-specific antigen) and by means of prostate palpation. However, these tests are not reliable enough to clearly diagnose prostate cancer. Indeed, once these steps have been completed, patients are then sent for a biopsy that reveals only 45% of positive cases. Moreover, nearly 10% of patients develop prostate infection after the biopsy. Once cancer is detected, different types of treatments are offered to patients. One of them is prostatectomy (surgery to remove the diseased prostate and the possibly affected lymph nodes), but it is not systematic. Increased patient monitoring is therefore necessary.
To date, no molecular biomarker that could easily detect such patients with non-aggressive (yet) dormant tumors has yet been determined. For this reason, a non-invasive diagnostic test and an active prostate cancer surveillance test would both be a real step forward in improving the quality of patient follow-up and care.

Antonin Morillon, Director of the Dynamic Genetic Information Unit and head of the Non-Coding RNA, Epigenetic and Genome Fluidity Team, proposes to validate a unique set of new “hidden” circulating biomarkers in order to develop a non-invasive, fast and robust urinary diagnostic test called PROSTATOR, which will focus on early detection of prostate cancer without unnecessary biopsy. Purpose of the research? To use the “hidden” part of the genome to find these new types of biomarkers. By using next-generation sequencing and innovative algorithms of artificial intelligence and bioinformatics, the team identified a set of uncatalogued sequences, which are significantly overexpressed in prostate cancer tumors.

This promising research project has just received the ERC “Proof of concept” grant: valued and prestigious financial assistance from Europe that directly enhances his potential to improve the diagnosis of patients with prostate cancer. Thanks to the ERC grant, Antonin Morillon will be able to go further and implement the PROSTATOR.

How does the PROSTATOR work?

During his first visit to the urologist or during active clinical monitoring, urine in the tube will be taken from the patient following the prostate examination. The doctor will send it directly to a laboratory to perform the PROSTATOR molecular test and to subsequently decide whether the patient needs to be scheduled for biopsy. This will prevent unnecessary biopsies, reducing the risk of psychological and physiological stress for patients, while helping us better control the associated costs borne by health systems. This test has the advantage of being fast and economical. “I am very proud and honored to have been awarded the ERC POC, because, apart from the fact that it is the financial assistance that we needed, it is also a true recognition of the efforts of my entire team. It rewards our work on transferring our basic research expertise to clinical application. This is really the starting point that will let us expand on our work and consider the creation of a start-up in the short term. The fact that Europe is so confident in our project is an encouragement to continue this process,” points out the researcher.

 

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Hydraulic fracturing in embryos

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Biologists from the Institut Curie and the CNRS together with a team of physicists from the Centre intedisciplinaire de recherche en biologie (Collège de France/CNRS/Inserm) shed light onto one of the mysteries of mammalian embryonic development.

Did you think hydraulic fracturing would be restricted to gas extraction? You would be wrong! The process does in fact also occur during embryonic development. This surprising finding has just been published by researchers from Institut Curie in Science.

Jean-Léon Maître (CNRS/Institut Curie) and his team of biologists conduct research on mammalian embryos, starting from the very first cell to the development of a whole organism.

In collaboration with a team of theoretical physicists at the Collège de France led by Hervé Turlier, Jean-Léon Maître and his colleagues examined how a liquid-filled cavity, known as the blastocoel, forms within the embryo during pre-implantation development, before attaching to the uterus. A few days after fertilization, when the embryo simply consists of a cluster of cells, a cavity forms within this cluster, pushing some of these cells into a ‘corner’ of the sphere. This step is key, as the position of this cavity plays a decisive role in building the mammalian body plan.

Small water pockets drain into the larger ones to form a single cavity

The researchers then experimented on mouse embryos: “The steps involved in pre-implantation development are very similar in mice and humans, in particular as far as the architecture of the embryo is concerned. The forces that shape these structures are probably the same in both species,” he explains. They used genetically-modified mouse embryos to label the adhesive bonds between cells, which become observable via high-resolution microscopy. As a result, they were able to see that hundreds of microscopic water pockets appeared between the cells, and that those formed by hydraulic fracturing. In other words, water rushes in between the cells, causing the more fragile bonds to break. By creating a hybrid embryo in which some of the cells were less sticky than the others, the researchers were even able to choose where these microcavities would form. Using theoretical modeling, scientists found that the pockets underwent a phenomenon similar to Ostwald ripening: larger pockets drew in the content of smaller pockets, with the latter gradually emptying until a single large cavity remained. This is the same mechanism, which explains the coarsening of bubbles in soapy foams.

This mechanical description of the embryo  illustrates the interdisciplinary nature of this study and the key contribution made by Hervé Turlier’s at the Collège de France. “This research could be used in assisted reproductive techniques (ART). About two-thirds of the transfers of in vitro fertilized embryos fail to implant. Any additional insight into pre-implantation development that we might glean could help us to improve those figures,” says Jean-Léon Maître.

Learn more :

Hydraulic fracturing and active coarsening position the lumen of the mouse blastocyst

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An Institut Curie team on the “iron throne”

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In just 48 hours, the abstract has been viewed 800 times and downloaded 160 times! The findings produced by Raphaël Rodriguez’s team at Institut Curie have the international science community on tenterhooks.

And that was exactly what the researcher had hoped for by publishing this extensive study on a platform for biologists before publishing it in a science journal: “The findings in themselves apply to a number of different fields, from biochemistry to epigenetics (see below), and the impact they have will be manifold in a range of areas, from cancerology to the cosmetics industry. This makes the findings difficult to publish in journals which are often too specialized – yet we wanted to make them available to researchers, to ensure they were visible and can be used as soon as possible,” he explained.

The young team leader has long focused on a glycoprotein (a protein with sugars attached to it) called CD44. The protein has been the subject of numerous studies, and has been detected in a great many organs, from ovaries and the liver to the prostate and pancreas. CD44 also plays a role in many different biological processes, such as embryonic development, inflammation, immune response and cancer. In the latter in particular, the protein has been linked to metastases and recurrences! But how? Raphaël Rodriguez and his colleagues have finally pinpointed the answer.

CD44 plays a role in iron endocytosis, meaning the process by which iron penetrates cells. This finding is made all the more unexpected by the fact that until now, there was only one known iron endocytosis mechanism, in which a specific protein, transferrin, transports iron, and its corresponding receptor, TfR1, deposits iron on the surface of cells.

The researchers demonstrated that when these cancerous cells become metastatic, this new method of transporting iron, linked to CD44, may well even be predominant. Once inside the cells, this iron acts as a key catalyst, essential to unlocking some gene expressions. In normal cells, chemically-modified and DNA-associated proteins called histones muffle some genes, and due to the iron, these “epigenetic” markers disappear. The researchers are already developing molecules capable of blocking iron being transported within the cells. New possibilities linked to these basic findings in the fight against cancer are therefore now within reach.

This research is the culmination of Institut Curie’s long-standing expertise, and in particular that of Jean-Paul Thiery, the former Director of the Translational Research department, Edith Heard, Research Unit Director and Collège de France Professor, and Geneviève Almouzni, Honorary Director of the Research Center, both epigenetics specialists.

Raphaël Rodriguez hopes that these findings will help him to pursue his research and encourage other teams to contact him with a view to exploring other aspects of this work, such as in the field of immunity, as CD44 plays a role in this process, or potentially in the field of cosmetics, as the process of iron endocytosis via CD44 also involves hyaluronic acid, already feted for its “rejuvenating” properties in skincare, and therefore better understood in terms of its actions.

 

NB : this study has not been published yet. Preprint available here

CD44 regulates epigenetic plasticity by mediating iron endocytosis

Sebastian Müller, Fabien Sindikubwabo, Tatiana Cañeque, Anne Lafon, Antoine Versini, Bérangère Lombard, Damarys Loew, Adeline Durand, Céline Vallot, Sylvain Baulande, Nicolas Servant, Raphaël Rodriguez

 

 

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Proteins: Exit This Way

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Cells secrete numerous proteins, but these proteins do not exit the cell surface from just anywhere, according to a study conducted jointly by two Institut Curie Research Center teams and published in the Journal of Cell Biology.

Stéphanie Miserey-Lenkei is a member of Bruno Goud’s Molecular Mechanisms of Intracellular Transport team and is interested in the role of the protein RAB6. RAB6 is found in the Golgi apparatus and regulates the protein secretion process within cells. Protein secretion is essential to the life of both cells and organisms. Proteins secreted by a given cell act as messengers in long-distance communication with other cells. They can also remain on the cell surface and provide anchoring points with the cell environment or points for interaction with other cells within the tissue.

Gaelle Boncompain, a member of Franck Perez’s Dynamics of Intracellular Organization team, which focuses on intracellular transport mechanisms, has developed tools to not only synchronize protein secretion (the RUSH system) but to block proteins at the point at which they leave the cell (the SPI system). These tools are now used by numerous other laboratories worldwide.

Working with their postgraduate students, the two researchers combined their expertise to show how secreted proteins follow very specific pathways within vesicles that guide them—as though on rails—from the Golgi apparatus to preferential secretion sites on the cell surface. Furthermore, they found that these sites are located exactly at the points at which cells attach to their environment. “We also observed that, regardless of the type of protein secreted, it is always the transport system involving RAB6 that is used. And the molecular motors involved and the microtubules, the “rails”, are the same,” explains Stéphanie Miserey-Lenkei.

In cancer, many studies have found that secreted proteins are transported abnormally. Cell surface proteins are involved in the migration and adhesion of cells within their environment. “It will be important to figure out the role played by the forces exerted by and on the cell, as well as to test the existence of these preferential secretion sites in three-dimensional cultures,” points out Gaelle Boncompain. The researchers still need to work out why these preferential secretion sites exist. They already have several hypotheses and their upcoming work should be able to tell us more. 

RAB6 and Microtubules Restrict Protein Secretion to Focal Adhesions

Lou Fourriere, Amal Kasri, Nelly Gareil, Sabine Bardin, Hugo Bousquet, David Pereira, Franck Perez, Bruno Goud, Gaelle Boncompain, Stéphanie Miserey-Lenkei

The Journal of Cell Biology May 2019, jcb.201805002; DOI: 10.1083/jcb.201805002

 

 

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The European Commission is supporting three doctoral training networks involving Institut Curie

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Of the 128 innovative training networks chosen by the European Commission as part of the Marie Sklodowska-Curie Actions, three involve teams from the Research Center. The projects will offer “high-level research and training opportunities” to doctoral candidates.

The chosen doctoral training programs “will contribute to improving the overall quality of doctoral training in Europe and beyond, adding to its innovative nature”, according to the European Commission when the results of its call for projects were announced in May 2019. The grant agreements are spread over four years.

Three of these Marie Sklodowska-Curie – International Training Networks (MSC-ITN) projects were obtained by teams at the Research Center at Institut Curie, including one as coordinator. The Marie Curie ITN Actions enable joint training for doctoral candidates, as part of a network of European partners and in a chosen scientific field.

The project leaders at Institut Curie are:

–              Marie Dutreix, head of the Repair, Recombination and Cancer Team, Charles Fouillade and Pierre-Marie Girard from her team, alongside Célio Pouponnot, co-lead of the Signaling and Tumor Progression Team, which is participating in the Theradnet network, coordinated by the University of Zürich (Switzerland), studying therapeutic radiation. This network includes the same teams as the Radiate-ITN network, which studied radiation, was just successfully completed, and obtained the same level of support from Europe. Their participation in the project is supported by the European Commission to the value of approximately €0.5 million.

–              Prof. Anne-Hélène Monsoro, head of the Signaling and Neural Crest Development Team, who is coordinating the NEUcrest network, involving 31 facilities and focusing on neural crest development. The overall budget of the NEUcrest project is €4.1 million. Institut Curie will directly manage approximately €0.5 million, not including the equivalent budget for management.

–              Angela Taddei, director of the Dynamic Nucleus Unit and head of the Nuclear Function Compartmentalization and Dynamics Team, who is participating in the Cell2Cell network, coordinated by the University of Munich in Germany, studying chromatin heterogeneity from cell to cell. It has been allocated a budget of nearly €275,000.

The total amount of support allocated to the Research Center as part of the MSC-ITN thus amounts to €1.37 million.