What are your research interests and
what is your area of expertise in pharmacology and GPCRs?

I really found in the translational research, a perpetual source of motivation to first understand some gliovascular pathologies from mechanistic but also therapeutic care management point of view. Then, the fundamental knowledge on membrane receptors, GPCRs and cell signaling appears essential to me to develop animal and cellular models to better understand the pathology of interest and the key role of GPCRs. More specifically, through collaborative research with clinicians, specialists in the field of GPCR-coupling and peptide chemists, we better understand the remaining controverted and enigmatic role of the urotensinergic system in some mechanisms, and established the antagonist/biased role of some synthetic urotensin II (UII) analogs at regulating the pleiotropic UT GPCR coupling. Because we never address enough the question of GPCRs pharmacology in various cell types, in different species, and in different physio and/or pathophysiological situations, I decided to generate transgenic knock-out and humanized UT knock-in mice thanks to OSEO –now bpi-france- and maturation programs. Moreover, while much oriented research focused on the vasoconstrictive activity of this peptide, without success, the option was to work from another angle and to test ligands of this GPCR at low concentration, and to look at different long-lasting endpoints (cell behavior), in order to consider UT, a vasoactive chemokine receptor, as a potential therapeutic target in pathological situations. Thus, we patented the impact of some UII analogs in inflammatory and cerebrovascular pathologies, then constituting for some of them, key lead compounds, that currently help developing new UT biased ligands. In particular, we showed that a UII analog, urantide, blocks glioma invasion, angiogenesis and growth, prevents death and cardiac dysfunctions of mice in septic shock and vasospasm and neurological deficit of mice with subarachnoid hemorrhage. This work opens interesting routes of investigation in the design of new UT biased ligands, pepducines or diagnostic/theragnostic UII based tracers for pathologies involving vascular inflammation and tumor cell migration/invasion.

What is your area of expertise in pharmacology and GPCRs?

My field of expertise concerns peptide GPCRs, more specifically those previously described to be expressed in both the vascular and astrocyte compartments of the brain, likely playing major roles in the neurovascular unit. But I was first interested in the potential impact of one of these GPCRs, UT, activated by the endothelial peptide ligands named urotensin-like peptides, and regulating dynamically or at long-term ionic channels such as the GABAA receptor in astrocytes. But this atypical system plunged me in the complexity of the action of two very similar endogenous ligands for one known GPCR exhibiting “annoying” binding properties (pseudo-irreversible), and coupling to various G proteins, that in addition, can be altered in pathological situations. This is through meetings with qualified, expert and nice collaborators (Drs Laurent Prézeau and Jean-Philippe Pin, IGF, Montpellier) from the GDR that I believe I have begun to understand the pharmacology of GPCRs. As you know, GPCR pharmacology is a long way, involving the affinity of GPCR for ligands, GPCR for G proteins, ligands for G proteins...

What is your scientific background?
How did you first hear of GPCRs?

I completed a PhD in neuroendocrinologyneurosciences on GABAAR receptor activity in neuroendocrine cells by the patch-clamp technique, in Rouen University, with Dr Hubert Vaudry (1996-2000). At that time, the neuroendocrinology was very active at deorphanizing GPCRs by peptide ligands and investigating integrated mechanisms. I was thus considering to study, how neuropeptides activating GPCRs, would control fast-dynamic neurotransmitter induced ionic changes, and then decided to join the lab of Pr David Colquhoun, University College London, UK, by means of a MRC fellowship, to acquire expertise in analysis and modelization of single ionic channels. I learned and mastered the fast-concentration jump technique to mimic electrical fast synaptic inputs on recombinant NMDA receptors. In parallel, I acquired expertise in molecular biology through mutagenesis of NMDA receptor subunits. This experience initiated a thought on "how can a rapid microscopic phenomenon as opening kinetics of a single channel in a simple membrane model, can be placed and transferred in integrated cellular and in vivo physiological systems?” I was recruited at Inserm in 2002 on a project aiming at understanding how one GPCR can control one ionic channel, in a physiological situation. To make emerging this de novo project, I realized that an appropriate scientific and technologic environment is absolutely essential.

Can you tell us about some “EUREKA” moments and surprises
in your past discoveries?

I probably thought encountering this type of “Eureka”, but finally, this exciting impression soon faded away in face of difficulties in implementing and demonstrating one mechanism. I have two recent examples in my mind. First it concerns the work we performed on the impact of the UII GPCR on glioma cell migration. In this domain, we learned “by walking” on how directional cell migration or chemotactic migration is a very complex mechanism. The question still pending at the present time is how a GPCR can detect a gradient concentration and orient the cell machinery to guide cells. I had the idea to look at the formation and maturation of the cell adhesion complexes and we observed that GPCRs finely tune these adhesions to allow directional migration, and that chemotactic migration is allowed by local dynamic regulation of adhesion in cells exhibiting an endogenous motile engine. But, at the time I understood that, very interesting and excellent papers were establishing this point by means of dynamic confocal microscopy and my Eureka has quickly become obsolete. The second example is more like a conceptual thing “that has to be shown” and it can be the work of a life time. It comes from the observation that many GPCRs may exhibit redundant activities in a single cell. It thus gets the idea that one GPCR activation, its associated signaling pathways, and cell behavior are dependent on the expression level of specific Gα, β or γ protein subunits, in a context of a physiological or pathological situation. It may seem like pushing an open door, but finally, it would be of a great interest to make a clear demonstration for therapeutic applications. .

Do you often pursue unconventional ideas? And if yes,
how do you canalize these ideas to form concrete scientific projects?

This is really funny, this is an issue for me especially. When I started research as a master student, I thought that the game was to find an unconventional idea and to test it, and this is probably not a good idea when one is novice. But I kept that in mind and spend the time trying to be “reasonable” because finally the current era does not allow testing ideas de novo, in term of financial resources and time (frequent evaluations of your activity, activity that you have to keep focused, etc…). Recently, I decided to try initiating two more original projects, i.e. how cancer-related secretome can impact cognitive functions, and how to capture invasive glioma cells in the brain to better fight cancer. This moderate risk taking was notably supported by “emergence call” from the Northwest canceropole, but clearly we would like more calls or support for these types of projects.

Congratulations for your new status of DR.
Does it change your life inside and outside the lab.
Do your students address you as “vous” now?

Thank you very much, I really admit that it was a real highlight in my career. I believe I can say that my research route wasn’t linear, I had always to find all means myself, in the broad sense, to conduct research. In 2008, I proposed to my current unit director to reconstitute a team, and initiate new projects. He trusted me, and it took more than 6 years, with many difficulties at finding grants, building the team and maintaining the direction for about 10 years, to become credible. This status of DR was probably more important for me than for the image its represents outside: hear “good job” arrived at the good time. This has had an impact I think on everyone in the team, because this encouragement was seen as the result of their work. With students, we are in a tight proximity, and this promotion did not modify our relationships.

What is the composition of your team and
what kind of training do your close collaborators have?

The team is composed of one Inserm director of research (M.C. Tonon), one PU (P. Gandolfo) and one MCF (F. Morin), three PU-PH and PH hospital researcher (V. Compère, E. Gérardin, O. Langlois), one IR CNRS (L. Desrues) and one IE Inserm (M. Dubois), one IE Inserm CDD, and we have currently the opportunity to recruit a MCF bringing I hope complementary expertise in electrophysiology and brain imaging. Furthermore, the team hosts 4 PhD students and a number of undergraduate students including clinicians (in Master 2) every year. This is here the great opportunity to tell that I’m very proud to work with them, surrounded by their competence and kindness. I see the team as a melting pot of skills and expertise that together will allow developing a continuum from cognitive to translational and applied projects.

You are implicated and you codirect the French platform ‘cancer and cognition”. Can you tell us about it?

This program “cancer and cognition” starts from the observations that cancer as well as its treatments (chemotherapy, targeted therapy) impact cognitive functions leading to syndromes called “chemofog”. Since 2007, the northwest Cancéropôle developed a research axis entitled “Cancer and Neurosciences” under the impulsion by Pr F. Joly (medical oncologist in the Center François Baclesse of Caen), to develop a unique program in France “Cancer and Cognition”. At this time, this echoed the many questions I asked myself about how to find the best therapeutic GPCR ligand, optimal in efficacy, without leading to side effects or comorbidities. Now, after 10 years, we developed expertise and animal models to investigate the impact of targeted therapy on brain functions and animal behavior. These aspects help us also to better think in term of drug design, testing and development, with this constant objective to propose the best molecule and treatment to patients. Moreover, from these questions, I went rapidly to the lay public, to patient associations and volunteers involved in the fight against cancer, thus giving us energy and enthusiasm to continue research.

You are recently moving in a new building named CURIB
(Centre universitaire de recherche et d’innovation biomédicale).
Is it stimulating to be in a new environment?

We just finished to relocate to this new building next to the previous place, named “Centre Universitaire de Recherche et d’Innovation en Biologie (CURIB), with a total area of 8 700 m2 funded by the Regional Council of Haute-Normandy and the FEDER (European funds for regional development). Our Unit now occupies 1800 m2 and is grouped with 3 other laboratories, 2 technological platforms and the new animal facility. This is currently a very exciting period and this larger space and the modern laboratory equipment will greatly facilitate our work and allow to better accommodate the ambition of our projects and the growth of our teams. At 15 min from the CHU Rouen hospital and 1h10 min from Paris by train, this center is definitely registered in the research dynamic of Normandy.

Through your scientific interests you meet and work with
pathologists and scientists from different disciplinary backgrounds.
Did you have to find a common language to be able to understand each others?

This multidisciplinary composition of the team, and the number of collaborations and meetings with clinicians is really something I wanted to create for our research. It’s true that we have not the same view of research. What is important: the global observation in a patient or the understanding of the molecular and cellular mechanism? In fact, both. Then I clearly had to adapt my mind and my way of being in face of the low availability of the practitioners and considered rapidly that it was “my job” to move regularly to the hospital, to generate work meetings, to propose projects and favor exchanges between young clinicians and scientists of the team. I did not find a common language, but rather adapt my research, the strategies, the objectives and my language depending on the situation. After some years working with our clinical partners, through training of younger practitioners in the team, it becomes obvious to work together, and to think about translational research programs on our main research topics.

You have received a grant for proof of concept from inserm to study
the therapeutic impact of biased ligands of UII receptor in subarachnoid hemorrhage.
How do you see this project in few years?
Do you plan to file patents,or to conduct clinical trials?

In subarachnoid hemorrhage (SAH), the mortality rate reaches as high as 30% within the first week, and 50% die in the first 6 months, with the main complication being delayed cerebral ischemia, due to cerebral vasospasm (CVS) and/or microthrombosis. I initiated this project 5 years ago with the clinicians of the team (anesthesiologists, neurosurgeons, neuroradiologists) to solve questions about patients, and by means of murine models of SAH we leveraged, the potential role of the urotensinergic system in the consequences of SAH. In a clinical pilot study we demonstrated that higher plasma UII level can be considered as a predictive marker of the onset of symptomatic vasospasm consecutive to SAH in human, and by means of wild-type and UT-KO-mice, we showed that UT constitutes a potential therapeutic target in SAH. We made the deposit of two French patents, and now thanks to the Inserm grant, we aim to fill an international patent with new UT ligands. This will be possible through a long-term and strong collaboration with Pr R. Leduc (Sherbrooke University, Quebec, Canada) and Dr L. Prézeau (IGF, Montpellier), with whom we previously investigated the biased signaling of UT. We currently investigate the in vitro and in vivo potential of new UT ligands at the UT-signaling pathways, and their preventing role on the vasospasm, neuroinflammation and neurological defects in humanized UT SAH mice. Thus, we really expect to propose that plasma UII dosage in the acute phase of SAH allows risk stratification and expedites the implementation of a treatment based on ligands targeting UT in SAH patients to allow improvement of patient outcome.

What would be in three words your advice to
PhD students and young researchers?

First of all, my student can testify that I am always prone to value the effort, because “le talent sans travail n’est qu’une sale manie” (citation) and that research innovations and discoveries need talented enthusiastic workers. Second, I would like to tell them to be curious about everything, opening their mind towards methodologies, fields, approaches, via interactions and reading papers. And then, always keeping doubts in the corner of the brain, never forget that we are just at a step of some discoveries, and that the reality is probably much more integrated and complex. To help that, you should like and culture the working with a multidisciplinary team members/environment/collaborators, listen to advice and warnings, and then you would be nurtured -and fed by- others.

Are you part of other GDR and science associations?
What does the GDR mean to you,
has it triggered collaborations with other GDR members?
Are there some things the GDR, its annual meeting or newsletter could improve?

I’m actively involved in the LARC-neurosciences network, board member of the northwest cancéropole (co-head of the cancer and neuroscience axis), and of course of Neuroscience and Neuroendocrinology French societies. I also now integrated the pre-clinical axis and the Onconeurotox program of the ANOCEF, and participate to many actions towards lay public with the Gefluc association of Normandy. The GDR GPCR 3545 was the first one I joined which gave me the opportunity to hear and face the best studies and methodological developments in the field of GPCRs in France and Europe, which has nothing to envy the international research. It was an arena for enthusiastic discussions with many collaborators in the area of GPCR modelization (as with Dr M. Chabbert, Angers), coupling or also involvement in pathologies. I think very much that the GDR is a very active and efficient network, and that the newsletter is grouping high quality information, this is the reason why I encourage my students participating and being involved in the writing of the letter. Now, through this structured network of excellence, it would be interesting to propose multicentered national collaborative GPCR projects such as “Programme d’actions intégrées de recherche (PAIR) that would be submitted to CNRS, INSERM or ANR.

Being born in Normandy,
how well did you adapt to the fog of London during your post-doc?
You came back to work in Normandy:
is it because you are more camembert than stilton?
More cider than beer? More seine that Thames?

It’s true that I was born in Normandy, but my roots came from Brittany, where I spent, most often as possible, part of my time. So you can imagine that I adapted quite well to the climate of London, and also to the enthusiastic dynamic of the city (pubs, parks, cosmopolite atmosphere…). Now you may understand my appeal for the fog in general, in London, in Normandy or in the brain (chemofog)! In fact, I came back to Normandy because one of the best laboratory in Neuroendocrinology was in Rouen. I like associating the useful to the pleasant, since it allows eating and drinking well, in a nice environment. Currently, Normandy is emerging as a very dynamic region, with a strong recognition in translational research.