CV Science

Helene Castel PhD in GPCRs and G proteins in gliomagenesis and brain vascular pathologies

Course and current status

Hélène Castel, PhD in Neuroscience,

French, 44 yrs, married, Three children

Current position - DR2 Inserm researcher at the Inserm Institute,

Team Leader “Astrocyte and Vascular Niche", U982 Inserm, DC2N lab, University of Rouen Normandie, France.

I started to develop different variants of the electrophysiological technique in the laboratory of Dr Vaudry (U413 Inserm) during my PhD, and biochemical approaches (Western-blot, second messengers measurement) to give a comprehensive view of modulation of receptor function by interacting proteins. Thereafter, I have spent 2 years on a post-doctoral position in the laboratory of Pr Colquhoun (Pharmacology Department, University College of London). There, I have developed fast-concentration-jump techniques to mimic electrical fast synaptic inputs on recombinant NMDA receptors. In parallel, I acquired expertise in molecular biology through mutagenesis of NMDA receptor subunits. When I obtained a permanent position as chargée de Recherche (CR) at Inserm (2002), my working project was based on the possible interaction between GABA_AR and other GPCRs in astrocytes.

1996-2000 - PhD student  in « Cell Biology, Neurosciences », Fellowships MENRT-teachings in the laboratory of Cellular and Molecular Neuroendocrinology, U413 Inserm, Rouen.

2000-2002 - Post-Doctoral position at University College London, Department of Pharmacology, London (Head-Pr D. Colquhoun). MRC recipient.

Since 2002 - Tenure Position, CR researcher at Inserm "the  Laboratory of Cellular and Molecular Neuroendocrinology”, U413 Inserm, University of Rouen, 76821, Mont-Saint-Aignan.

Since 2010 - Head of the team “Astrocyte and Vascular Niche in cell differentiation and Gliomagenesis within the DC2N Lab, U982 Inserm, University of Rouen, Normandy, France.

Prize - Prize of the LARC-Neurosciences Network (1999), of SNE-SERVIER (2000), and of “Ecole doctorale Normande Chimie-Biologie” (2000).

Certificates - Hygiene and safety (1995), Accreditation for investigation on animals n° 76-98 (2008), Surgery Level (2014).

Teaching - Masters 1 and 2 “Biologie-Santé” (2003-2010), 40h eq. TD/y.

Thesis and Master Supervision - More than 30 Master 2, including 12 clinicians, and 6 PhD, past and present

 Evaluation committees

2000- ... Member of French Neurosciences and Neuroendocrinology society, ANOCEF, GDRGPCR3545, GLISTEN. 2002-2005. Member Joint Administrative Committee (CAP) n° 2 Inserm. 2007-2015. Member of Specialist Commissions: (section 66-69) University of Rouen (2007-2009), Amiens (2009), Caen (2009), Lille (2011), Rouen (2012 and 2015) and selection committee "Chair of excellence "Rouen (2010-2011). Thesis and HDR Reviewer. 2008-2012. Elected member of Specialized Scientific Committee Inserm (CSS 1), Neurosciences.

2008- ... Member of the Scientific Steering Committee Cancéropôle Northwest. 2010- ... Expert for the Normandy Ethics Committee, ANR Bioémergence, Call offers Clinical Research of Marseille, Tyrolean Science Foundation, Cancéropôles PACA and Northwest, Aquitaine Region, scientific journals.

2012- ... Member Research Committee in Biomedical and Public Health Rouen Hospital. 2013- ... Member of the Inserm Evaluation Commission Contracts Hospital Interface. 2014- ... Member of the Jury of innovative business Bpifrance, Normandy. 2014- ... ad hoc consultant for Novartis International.

2015- ... Member of the Scientific board League against Cancer charity. 2015- ... Member of the Scientific board of the International Cancer and Cognition Task Force.

Scientific summary

The team was created in January 2010, is composed of 2 Inserm researchers, 1 Professor, 1 Assistant Professor, 5 MD’s (PhDs) with clinical activity, 2 Inserm and CNRS engineers, 1 post-doc, 1 IE on contract and 4 PhD students. Furthermore, it hosts a number of undergraduate students including cliniciens (Master 2) every year. The reinforcement of the team with active clinicians allowed the establishment of translational and applied research projects.

The goal of the team is to explore the role of neuropeptides, in particular urotensin II (UII), expressed at the gliovascular interface in pathophysiological contexts, i.e. the astroglioma development and the sub-arachnoid hemorrhage (SAH). We ambition to underpin the therapeutic potential of G protein-coupled receptors (GPCRs) exhibiting both chemokine and vasoactive properties and involved in cell migration, differentiation/dedifferentiation and/or transdifferentiation. Our achievements lie on the demonstration of i) the pleiotropic behavior of the UII receptor (UT) upon activation by endogenous peptides or synthetic peptide analogs, ii) the establishment of common expression pattern and behavior (autophagy, cell adhesion and migration) between chemokine and urotensin systems in glioma and, iii) the key role of the urotensinergic system in cerebral vasospasm and neurocognitive deficits post-SAH in human and mouse preclinical models.

The project aims focusing on “chemotactic GPCRs and G protein couplings in glioma development” involving epithelial-like to mesenchymal transdifferentiation (EMT-like) and on “the chemotactic peptide UII system during the brain vascular pathology SAH” involving endothelial cell transdifferentiation (EndMT). Our preliminary analyses suggest that GPCR activities in such pathological conditions may undergo a signaling switch controlled by changes in the expression levels of G-protein subunits, leading to specific α and βγ combinations. We will address these issues through strong collaborations to i) develop UT specific ligands and design peptidomimetics and pepducins, ii) modelize G protein subunit combinations and study their functions, and iii) analyze glioma cell fate in vitro and in vivo.

This project offers several opportunities for the development of effective therapies by targeting chemokine GPCRs or G protein nods and consequently the downstream effectors involved in gliomagenesis or brain vascular pathologies.

 Key publications

1. Joly, F., Heutte, N., Duclos, B., Noal, S., Léger, I., Dauchy, S., Longato, N., Desrues, L., Lange, M., Sevin, E., Rieux, C., Clarisse, B., Castel, H. and Escudier, B.: Prospective evaluation of the impact of antiangiogenic treatment on fatigue and cognitive functions in metastatic renal cancer. Eur. Urol. Focus (in press).
   
2. Coly, P.M., Perzo, N., Le Joncour, V., Lecointre, C., Schouft, M.T., Desrues, L., Tonon, M.C., Wurtz, O., Gandolfo, P., Castel, H. and Morin, F. : Chemotactic G protein-coupled receptors control cell migration by repressing autophagosome biogenesis. Autophagy (in press)
   
3. Lecointre, C., Desrues, L., Joubert, J.E., Perzo, N., Guichet, P.O., Le Joncour, V., Brulé, C., Chabbert, M., Leduc, R., Prézeau, L., Laquerrière, A., Proust, F., Gandoldo, P., Morin, F. and Castel, H. : Signaling switch of the urotensin II vasoactive peptide GPCR : Prototypic chemotaxic mechanism in glioma. Oncogene 34:5080-5094 (2015).
4. Joly, F., Giffard, B., Rigal, O., Lange, M., LeFel, J., Schagen, S., Ahles, T., Vardy, J., Pancré, V., Dubois, M. and Castel, H. : Impact of cancer and treatments on cognitive functions: Update of the advances in research from the Paris International Cognition and Cancer Task Force Symposium. J. Pain Sympto. Manage 50:830-841 (2015)
5. Jarry, M , Lecointre, C., Malleval, C., Desrues, L., Schouft, M.T., Le Joncour, V., Liger, F., Lyvinec, G.,  Joseph, B., Loaëc, N., Meijer, L., Honnorat, J., Gandolfo, P. and Castel H. :  Impact of meriolins, a new class of cyclin-dependent kinase inhibitors,on malignant glioma proliferation and neo-angiogenesis. Neuro Oncol. 16:1484-1498 (2014).
6. Brulé, C.*, Perzo, N.*, Joubert, J.E.*, Sainsily, X., Leduc, R.**, Castel, H.** and Prézeau, L.** : Biased signaling regulates the pleiotropic effects of the urotensin II receptor to modulate its cellular behaviors. FASEB J. 28:5148-5162 (2014). *, co-first authors; **, co-last authors
7. Clavier, T., Tonon, M.C., Foutel, A., Besnier, E., Lefevre-Scelles, A., Morin, F., Gandolfo, P., Tuech, J.J., Quillard, M., Veber, B., Dureuil, B., Castel, H. and Compère, V.: Increased plasma levels of endozepines, endogenous ligands of benzodiazepine receptors, during systemic inflammation and sepsis: a prospective observational study. Crit. Care, 18(6):633 doi: 10.1186/s13054-014-0633-7  (2014).
   
8. Dubois, M., Lapinte, N., Villier V, Lecointre, C., Roy, V., Tonon, M.C., Gandolfo, P., Joly, F., Hilber, P. and Castel, H.: Chemotherapy-induced long-term alteration of executive functions and hippocampal cell proliferation: Role of glucose as adjuvant. Neuropharmacology 79:234-248 (2014).