Team 5: Genetics, Biology, and Plasticity of Brain Tumors

Team leader : Hélène Castel

Research Activites

Publications

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Research activities

The NeuroGlio team develops a fundamental, genetic, and translational program in Neuro-oncology, aiming to understand the immuno-inflammatory or immunosuppressive mechanisms of peripheral and cerebral cancers such as adult and pediatric gliomas, and the contribution of the immune and nervous microenvironments to treatment resistance. In this global project, we search for original targets and test new therapeutic strategies and immunotherapies to combine therapeutic efficacy with the preservation/rehabilitation of cerebral and cognitive functions. We work on two complementary axes:

Brain Tumors, Microenvironment and Therapeutic Strategies
- Establish an ambitious and innovative research program on genetic risk factors (Li-Fraumeni, etc.) for brain tumors, particularly pediatric ones, using cerebral organoids. We have highlighted alterations in neurodevelopment and cytokinesis in complex and vascular cortical organoids, as well as choroid plexus or cerebellum organoids, and currently investigate therapeutic tools and strategies, as well as neurotoxicity.
- Study the role of mechanical constraints in the vascular and immune niches on glioblastoma recurrence using scRNAseq and proteomic methods.
- Test and demonstrate the role of G protein-coupled receptors (GPCRs) (urotensin II receptor, etc.) in cerebral pathological pathways involving brain blood barriers such as subarachnoid hemorrhage or angiogenesis in glioblastoma, in murine preclinical models, KO or KI humanized for the receptor of interest (UT receptor).
- Evaluate specific, biased compounds or ligands of these receptors or receptor oligomers in the prevention and/or treatment of inflammatory and cerebrovascular pathologies, in vitro in recombinant cellular models and in vivo in murine preclinical models.
- Show the impact of G proteins or platform proteins (Filamin A) on glioblastoma invasion and aggressiveness in 2D and 3D culture models and tumoroids prepared from patient glioma samples.
- Finely study the intracellular vesicular trafficking orchestrated by autophagy proteins ATG5 and ATG9A, and the ATG9 partner proteins overexpressed in the mesenchymal subtype of glioblastoma and associated with a poor prognosis, using STED and TIRF methods.
- Target the mechanisms of glioblastoma invasion and recurrence, and the role of the nervous microenvironment, particularly how hyperexcitability, axonal conduction, and white matter favor glioblastoma growth (electrophysiological recordings of axonal activities and optogenetic methods).
- Study possibilities for local therapy by modifying the immunosuppressive environment of glioblastoma through injections of matrices, biomaterials, and hydrogels into the glioblastoma resection cavity; the goal is to create tumor traps using chemokines, control the inflammatory status of tumor macrophages and allow for tissue repair during treatment.
Impact of Cancer and Cancer Therapies on Neurobiological and Cognitive Functions
- Study the role of new-generation hormonal therapies on emotional reactivity, cognitive functions, and neurofatigue in aged mice, and the impact of a chemotherapy on the dysregulation of the gut microbiota balance, systemic inflammation, and neuroinflammation, responsible for “neurofatigue” and cognitive deficits.
- Demonstrate the role of cancer extracellular vesicles on cognitive functions and neuroinflammation in tumor-bearing preclinical behavioral models.
- Evaluate organoid models of brain cancer (glioma) or pancreas cancer, the role of nervous regulation on tumor growth using cancer-nerve/cortex assembloids, as well as behavioral animal models.

The strength of the NeuroGlio team lies in complementary and multidisciplinary expertise in molecular and cellular biology targeting the migration and invasion of cancer cells, in the design and validation of dynamic cell imaging tools, in the establishment of behavioral murine cancer models, in electrophysiology on organotypic slices and in vivo, and even in optogenetics, as well as in the development of organoids and cerebroids—strategies and models that we wish to use for our research projects on cerebral oncogenesis and evaluation/prevention of brain toxicities.

Flagship publications

Patent- WO/2025/087667; PCT/EP2024/077717: Castel, H., Mutel, A., Morin, F., Lecointre C., Bonin M.C., Leduc, R. Construct comprısıng or consıstıng of a peptıde sequence capable of ınhıbıtıng the ınteractıon of fılamın a wıth the UT receptor – pharmaceutıcal composıtıon and related products. Start-up planned with Normandie Valorization.

Nicola C, Pedard, Dubois M, Desrues L, Neveu P, Riou G, Johnston I, Dembele PK, Lecras P, Vaudry D, Adriouch S, Joly F, Hilber P, Wurtz O, Castel H. Anti-PD-1/PD-L1 Therapy Triggers Cognitive Deficits and Anxiety-Like Behaviors Through Tumor-Initiated Neuroinflammatory Niches in Male Mice. Bioarchive. doi.org/10.1101/2025.09.03.673981.

Pedard L, Prevost, Carpena C, Holleran B, L, Dubois M, Nicola C, Gruel R, Desrues L, Godefroy D, Deffieux T, Tanter M, Ali C, Leduc R, Prézeau L, Gandolfo P, Morin F, Wurtz O, Bonnard T, Vivien D and Castel H. Early expression of the urotensin II receptor in meninges drives cerebrovascular disorders, perivascular macrophages and neuroinflammation in subarachnoid hemorrhage. NATURE COMMUNICATIONS, accepted.

Parment R, Dubois M, Desrues L, Mutel A, Dembélé KP, Belin N, Tron L, Guérin C, Coëffier M, Compère V, Féger C, Joly F, Hilber P, Ribet D, Castel H. A Panax quinquefolius-Based Preparation Prevents the Impact of 5-FU on Activity/Exploration Behaviors and Not on Cognitive Functions Mitigating Gut Microbiota and Inflammation in Mice. CANCERS (Basel). 2022 Sep 10;14(18):4403. doi: 10.3390/cancers14184403. PMID: 36139563; PMCID: PMC9496716.

Campisi D, Desrues L, Dembélé KP, Mutel A, Parment R, Gandolfo P, Castel H, Morin F. The core autophagy protein ATG9A controls dynamics of cell protrusions and directed migration. JOURNAL CELL BIOLOGY. 2022 Mar 7;221(3):e202106014. doi: 10.1083/jcb.202106014. Epub 2022 Feb 18.

Kasapidou PM, de Montullé EL, Dembélé KP, Mutel A, Desrues L, Gubala V, Castel H. Hyaluronic acid-based hydrogels loaded with chemoattractant and anticancer drug – new formulation for attracting and tackling glioma cells. SOFT MATTER. 2021 Dec 15;17(48):10846-10861. doi: 10.1039/d1sm01003d.

Nicola C, Dubois M, Campart C, Al Sagheer T, Desrues L, Schapman D, Galas L, Lange M, Joly F, Castel H. The Prostate Cancer Therapy Enzalutamide Compared with Abiraterone Acetate/Prednisone Impacts Motivation for Exploration, Spatial Learning and Alters Dopaminergic Transmission in Aged Castrated Mice. CANCERS (Basel). 2021 Jul 14;13(14):3518. doi: 10.3390/cancers13143518.

Le Joncour V, PO, Dembélé KP, Mutel A, Perzo N, Campisi D, Desrues L, Modzelewski R, Couraud PO, Ferracci FX, Marguet F, Laquerrière A, Vera P, Bohn P, Langlois O, Morin F, Gandolfo P* and Castel H. Targeting the urotensin II/UT G protein-coupled receptor to counteract angiogenesis and mesenchymal hypoxia/necrosis in glioblastoma. FRONTIERS in CELL DEVELOPMENT and BIOLOGY, 2021, 10.3389/fcell.2021.652544.

Poret B, Desrues L, Bonin MA, Pedard M, Dubois M, Leduc R, Modzelewski R, Decazes P, Morin F, Vera P, Castel H, Bohn P, Gandolfo P. Development of novel 111-In-labeled DOTA urotensin II analogues for targeting the UT receptor overexpressed in solid tumours. BIOMOLECULES, 2020, 10: 471.

Coly PM, Perzo N, Le Joncour V, Lecointre C, Schouft MT, Desrues L, Tonon MC, Wurtz O, Gandolfo P, Castel H, Morin F. Chemotactic G protein-coupled receptors control cell migration by repressing autophagosome biogenesis. AUTOPHAGY, 2016, 12:2344-2362.

Lecointre C, Desrues L, Joubert JE, Perzo N, Guichet PO, Le Joncour V, Brulé C, Chabbert M, Leduc R, Prézeau L, Laquerrière A, Proust F, Gandolfo P, Morin F and Castel H. Signaling switch of the urotensin II vasosactive peptide GPCR: prototypic chemotaxic mechanism in glioma. ONCOGENE, 2015, 34:5080-94.