Invacell: Philippe Chavrier and Harald Stenmark labs received grant to collaborate on cancer invasion and metastases research
Philippe Chavrier and his colleagues have received a joint grant with Norwegian researchers from the group of Harald Stenmark from The Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. The funds were donated by Trond S. Paulsen and allocated by The Radium Hospital Foundation to combat cancer cell invasiveness through the project Invacell.
The project is a basic research work that facilitates the development of drugs in the long term that can prevent the spread of metastases. The research will run over four years and contribute to strengthening the long-term cooperation between Norway and France. The project has been created simultaneously with a newly established framework agreement for cancer research between Oslo University Hospital and Institut Curie.
Philippe Chavrier and his colleagues at Institut Curie have long-standing interest in understanding the mechanism of tumor invasion in breast cancer. Their studies on MT1-MMP and invadopodia in breast cancer invasion were crucial contributions to the foundation of the collaboration.
The physicist Pascal Hersen, new director of the Curie Physical Chemistry unit
Pascal Hersen, CNRS director of research in biophysics, has taken over as director of the Curie Physical Chemistry unit (UMR 168 CNRS/Institut Curie). Following a call for tenders, his application was supported by an international recruitment committee and by the Scientific Advisory Board of Institut Curie, and approved by the director of the Research Center. He replaces Axel Buguin, interim director of the unit following the sudden death of Maxime Dahan in 2018.
Until now, Pascal Hersen (PhD), 42 years old, headed an interdisciplinary team of around fifteen researchers at the Laboratoire matière et systèmes complexes in the Physics Department at Université Paris Diderot. His work is in a new field of research – cybergenetics – which involves determining how cells process information, how they adapt dynamically to changes in their environment and to what extent it is possible to control the cellular processes. This physicist joins the Institut Curie Research Center to head up the Curie Physical Chemistry unit (UMR 168 CNRS/Institut Curie).
The work of the Curie physical chemistry unit, whose aim is to propose a physics-related vision of the fundamental processes at work in living cells, using methods and concepts from experimental and theoretical physics, and the work in the field of cybergenetics conducted by his team joining the unit, will be mutually enhanced. “We are developing computerized feedback loops to control the level of gene expression in real time at the single-cell level. This new technological approach combines microfluidics, microscopy, synthetic biology, optogenetics and theory of control,” he explains, “and we are looking to determine whether or not to apply this approach to a variety of contexts from controlling gene expression in single cells to spatial orchestration of multicellular dynamics.”
“Within the unit, and without prejudice to the interactions with the other research units, a great many collaboration projects are taking shape,” comments Prof. Axel Buguin, interim director of the unit since the death of Maxime Dahan last July. “The research subjects perfectly match those developed in the unit involving quantitative biology. They will benefit from our involvement in the Institut Pierre-Gilles for microfluidics.” For one year, Prof. Buguin, who was deputy director alongside Maxime Dahan, worked tirelessly to manage the transition and prepare for the future of the research unit and the some 120 people working there. It has been decided that Mathieu Coppey, head of the Cellular organization and imaging team (LOCCO), will be the unit’s deputy director.
Encouraged by meetings with team leaders in the unit, as well as with most of the research unit directors on the Paris site of the Research Center, the new unit director was able to observe the “wonderful interdisciplinary and collaborative approach, as well as a rich ecosystem of resources and researchers. Within this exceptional context, the unit will strive to contribute to the Curie research-care continuum model by developing innovative research projects focused on the physics of cancer, from understanding the elementary behavior of cells and tissues, to the medical applications.”
Pascal Hersen has authored over 40 peer-reviewed publications, filed two patents and helped create a start-up. He is the beneficiary of an ERC Consolidator grant (SmartCells). He was involved in founding the Centre de recherche interdisciplinaire (CRI), today attached to the University of Paris, and was auditor for the Institut des hautes études pour la science et la technologie (IHEST).
A new player in the regulation of epigenetics
The team of Raphael Margueron, together with that of Deborah Bourc’his and other international teams, highlighted the role of a new key player in the regulation of genes and its dysfunction that can lead to different diseases.
Gene expression, i.e. the control of their use by a given cell at a given time, responds to complex mechanisms. A group of proteins called Polycomb contributes to the orchestration of genes, reducing them to silence when they should be inhibited by the phenomenon called epigenetics. “In mammals, the “Polycomb machinery” is composed of dozens of proteins,” says Raphael Margueron, researcher at Institut Curie (U934 INSERM/CNRS UMR3215). His team is taking a close interest in this group and other players that are moving around to indicate to the Polycomb group proteins which genes should be blocked from expression.
In this context, Raphael Margueron and his colleagues have worked to highlight the role of a previously unknown player in these processes: EZHIP. Its intervention is necessary for the maturation of female gametes (reproductive cells). Their discovery published in Nature Communications comes at the same time that other teams have revealed the role of EZHIP in many types of children’s brain cancer. Highlighting their scientific and medical interests, these different revelations were put into perspective in the Nature journal where the authors note that “these studies lay the groundwork for exploring the role of this protein in triggering cancer and indicate that targeting PRC2 or EZHIP may have therapeutic potential for children with [these cancers]”. With these promising advances, “we will continue to study this co-factor to understand why it is so important,” promises Raphael Margueron.
A “molecular motor” reveals unsuspected strengths
Anne Houdusse, a specialist in “molecular motors” at Institut Curie, revealed in Nature Communications a new mode of action of these motors involved in malaria infection. A disease that annually kills half a million people worldwide.
For over 25 years Anne Houdusse (UMR 144 CNRS / Institut Curie) has focused her research on molecular motors: proteins capable of developing mechanical forces and producing movements. It is through these molecular motors that our muscles contract, for example, but it’s also thanks to them that cancer cells can be triggered to metastasize…
The researcher has become an international reference on the subject. The proof? “When several scientists in the United States and England began to suspect the involvement of one of these molecular motors, Myosin A, in the infection with Plasmodium [the malaria parasite], they contacted each other simultaneously,” she explains. The researchers then organized themselves into a consortium and revealed the precise role of Myosin A in this context.
“Experts in visualizing motors at atomic resolution, we also gained expertise in the development of small molecules to block the operation of these engines. Our goal is to understand their role in health and disease,” she further explains.In the case of the Plasmodium Myosin A, we uncovered the details of its atypical mechanism for force generation. We understood how the motor can adapt the force produced for different essential functions of the parasite: the invasion of red blood cells and the rapid spread of the parasite to other stages of its cycle. ” These results make it possible for us to develop new treatments against malaria by targeting the key driver – Plasmodium Myosin A.
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.
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.
Identifying two genes involved in regulating stem cells
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.
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.
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.
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.
Antonin Morillon, winner of the ERC “Proof of concept” scholarship
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.