Role of the JMY protein in human brain development and glioblastoma stem cell radioresistance: from brain organoids to therapeutic screening
The JMY protein is an important regulator of the actin cytoskeleton, involved in cell migration and morphogenesis. Expressed in the developing brain, it is associated with several key processes of neurogenesis, including neurite formation, dendritogenesis, myelination, and neuronal migration. However, its specific role in human brain development remains poorly characterized.
In parallel, our work demonstrates that JMY plays a central role in the pathophysiology of glioblastoma, a highly aggressive brain tumor. Following irradiation, glioblastoma stem cells increase their migratory and invasive capacities through a pathway involving HIF1a and JMY. This activation promotes the formation of actin-rich structures known as tumor microtubes, which are associated with therapeutic resistance.
This project aims to investigate JMY as a common regulator of neurodevelopment and tumor plasticity.
In a first axis, we will analyze the impact of JMY deficiency in human brain organoids derived from iPS cells, in order to assess its effects on proliferation, differentiation, neurogenesis, and cortical organization.
In a second axis, a high-throughput pharmacological screening will be conducted to identify inhibitors capable of blocking radiation-induced migration of glioblastoma tumor stem cells.
The expected results will improve our understanding of JMY’s role in the human brain and support the development of new strategies aimed at limiting glioblastoma recurrence after radiotherapy.
The multiple roles of cohesin in genome stability
Cohesin, a ring-shaped protein complex, is crucial for genome stability, gene expression, sister chromatid cohesion, and DNA repair. It forms intrachromosomal loops during interphase, aiding in chromatin organization by bringing enhancers and promoters together. Cohesin also ensures sister chromatid cohesion during DNA replication and repairs double-strand breaks (DSBs). In response to DNA damage, cohesin binds to DSBs and enhances cohesion via damage-induced cohesion (DI-cohesion). Our recent findings show that cohesin tethers DSB ends through oligomer formation (Phipps et al., 2025).
This research project aims, in the frame of an ANR funded project, to explore how DNA damage influences cohesin’s functions in genome stability. The main hypothesis is that DNA damage activates distinct cohesin populations with specific roles critical for maintaining genome integrity. Using Saccharomyces cerevisiae as a model, the project focuses on three goals: analyzing the impact of DNA damage on cohesin composition and modifications, studying oligomerization in DSB tethering, and identifying the cohesin populations involved in DI-cohesion.
The methodology combines biochemical, genetic, and genomic approaches. Key tasks include identifying new cohesin interactors, analyzing cohesin in specific mutants, and investigating post-translational modifications.
This project aims to provide comprehensive insights into cohesin’s diverse roles in genome stability beyond traditional sister chromatid cohesion.
Development of monoclonal antibodies for the diagnostic and the treatement of hypervirulent-Klebsiella pneumoniae
For several years, we have observed the emergence of hypervirulent (hvKp) strains of Klebsiella pneumoniae that have become highly resistant to antibiotics. In a context of dwindling antibiotic options, monoclonal antibodies (Abs) directed against well-conserved capsular antigens of these hvKp strains appear as a promising therapeutic alternative.
This PhD project is structured around three complementary objectives:
1. To describe the circulation of hvKp clones through comparative genomic analysis of strains collected via the French National Reference Center for Antibiotic Resistance and through an international collaboration.
2. To produce and characterize monoclonal Abs directed against the HvKp capsule.
3. To develop a rapid detection tool based on MALDI-TOF profile analysis coupled with machine learning algorithms.
Acellular Biotherapy with Optimized Immunomodulatory Properties for the Prevention of Organ Injury in Traumatic Contexts
Severe trauma causes more than 5.8 million deaths worldwide each year, often associated with massive hemorrhages and multiple organ failure (approximately 33% of cases). Rhabdomyolysis, common in these patients, results from the destruction of muscle cells and leads to the release of their contents into the bloodstream. This complication promotes acute kidney injury and liver dysfunction. Currently, no specific treatment exists; management remains primarily symptomatic. Mesenchymal stromal cells (MSCs) are widely used for their immunomodulatory and regenerative properties. Preclinical studies have shown that IL-1ß-preconditioned MSCs can prevent kidney and liver damage and reduce vascular permeability after hemorrhagic shock. Their efficacy relies on the secretion of soluble factors and extracellular vesicles, known as acellular products. A large-scale, clinical-grade production method for these products, based on tangential flow filtration, has been developed. These products exhibit experimentally demonstrated immunomodulatory activity and hepatoprotective effects. Ready to use and easy to store, they represent a promising alternative to cell therapies in emergency settings. The objective of this thesis is to optimize the immunomodulatory and anti-inflammatory properties of these cell-free products by promoting their expression of two key immune tolerance molecules, PD-L1 and HLA-G. We will evaluate the interactions between these optimized products and various immune cells in vitro, and then in vivo in a traumatic hemorrhagic shock model (rat model).
Influence of Cytomegalovirus on Tissue-Specific Immune Responses in Non-Human Primate
Most studies in anti-infectious immunity focus on characterizing pathogen-specific immune responses and identifying strategies to optimize them. It is now essential to consider interindividual variability related to age, sex, metabolic status, and infectious history, which strongly influence these responses.
IDMIT’s expertise in preclinical modeling of viral infections provides an ideal framework to address these questions. Cytomegalovirus (CMV) infection represents a relevant model due to its high prevalence, its age-dependent effects, and its association with immune aging. Although epidemiological data suggest that CMV seroprevalence impacts responses to other infections and to vaccination, the underlying mechanisms remain poorly understood. We hypothesize heterogeneous effects related to the diversity of host–virus interactions across sites of viral persistence.
This project aims to characterize CMV-specific immune responses in blood and tissues of young and aged non-human primates, and in the context of chronic SIV infection. The objectives are (i) to assess age-related differences in viral dissemination and immune responses, (ii) to evaluate the predictive value of blood markers relative to tissue parameters, and (iii) to study the reciprocal modulation of CMV and SIV responses during co-infection.
These studies will contribute to the development of vaccination strategies targeting the deleterious effects of CMV and the tissue-specific modulation of immune responses.
Origins and evolution of prion-like proteins (PrLPs) in eukaryotes
Initially associated with neurodegenerative diseases, prion-like proteins (PrLPs) are now recognized as key physiological players in cellular plasticity and stress response. These proteins often contain an intrinsically disordered domain rich in glutamine and asparagine, known as a prion-like domain (PrLD), capable of switching between soluble, condensed, or amyloid states. Notable examples include CPEB in Aplysia, involved in synaptic memory, MAVS in antiviral defense, MED15 and FUS in transcriptional regulation and nucleocytoplasmic condensate dynamics, and ELF3 in plants, whose amyloid polymerization controls flowering and photoperiodic responses. In fungi, Sup35, Ure2p, and HET-s serve as experimental models of functional prions, demonstrating that reversible aggregation can act as a regulatory or adaptive mechanism. These conformational transitions are now viewed as adaptive molecular strategies rather than pathological anomalies.
This PhD project aims to trace the origin and diversification of prion-like proteins across eukaryotes, testing the hypothesis that major paleoclimatic crises have episodically promoted the emergence and duplication of genes encoding PrLDs through microsatellite expansion and transposable element activity. The project will combine large-scale phylogenomic analyses, PrLD domain detection, and modeling of selective pressures to map the key stages in the functional evolution of PrLPs and their links to stress tolerance.
Combination of ionizing radiation and radio-enhancing molecules in breast cancer models
The proposed program aims to evaluate the efficacy of molecules enhancing the effects of radiotherapy, in models of breast cancer. Several molecules targeting and inhibiting the Base Excision Repair pathway will be tested for radiopotentiation efficacy in the in vitro and in vivo models.
The proposed inhibitors are already being investigated in vitro, both in the laboratory and by collaborators. We have shown that inhibition of the mechanisms targeted leads to an impairment in DNA damage repair following genotoxic stress. During this project, we will evaluate the effects of inhibitors on DNA damage repair induced by irradiation of different types (conventional, ultra-high dose rate, even extreme dose rate) and the associated mechanisms.
Variability in response to therapeutic combinations is frequently observed when moving from in vitro to in vivo models. We will therefore evaluate the inhibitors on cell line models well characterized in the laboratory, and corresponding to different breast cancer subtypes. On the other hand, the studies will be completed by a validation of the effects observed in vitro on a murine model of breast cancer. This xenograft model, developed in immunocompetent animals, will enable us to monitor the clinical, histological and immune response of the animals and their tumors, in order to confirm the interest of the molecules for therapeutic application in support of radiotherapy.
The proposed program will benefit from the laboratory's collaborations with physicists and chemists, and IRCM's experimental facilities and platforms (irradiation, animal experimentation, microscopy, cytometry, etc.).
Exploring mechanisms of action of vaccine induced protection against infectious diseases in humans
The project aims at unravelling the molecular and cellular mechanisms that contribute to long-term protection induced by vaccines. Early changes (hours and days) occurring at site of injection and distant sites following vaccine injection will be correlated to long lasting (beyond 12 months) induction of neutralizing antibodies and specific T and B cell memory. A particular focus will be made to the relation of immune response with vaccine antigen persistence in the organisms. Multiple omics approaches will be applied to different tissue compartments of animals vaccinated with the yellow fever vaccine (Stamaril) known to induce a remarkable durable response, to then inform the design of new generation of anti-poxvirus vaccines.
Dynamic interplay of Rad51 nucleoprotein filament-associated proteins - Involvement in the regulation of homologous recombination
Homologous recombination (HR) is an important mechanism for the repair of ionizing radiation- induced DNA double-strand breaks. A key step in HR is the formation of Rad51 nucleoprotein filaments on the single-stranded DNA that is generated from these breaks. We were the first to show, using yeast as a model, that a tight control of the formation of these filaments is essential for HR not to induce chromosomal rearrangements by itself (eLife 2018, Cells 2021, Nat. Commun. 2025). In humans, the functional homologs of the yeast control proteins are tumor suppressors. Thus, the control of HR seems to be as important as the mechanism of HR itself. Our project involves the use of new molecular tools that allow a breakthrough in the study of these controls. We will use a functional fluorescent version of the Rad51 protein, developed for the first time by our collaborators A. Taddei (Institut Curie), R. Guérois and F. Ochsenbein (I2BC, Joliot, CEA). This major advance will allow us to observe the influence of regulatory proteins on DNA repair by microscopy in living cells. We have also developed highly accurate structural models of control protein complexes associated with Rad51 filaments. We will adopt a multidisciplinary approach based on genetics, molecular biology, biochemistry, and protein structure to understand the function of the regulators of Rad51 filament formation. The description of the organization of these proteins with Rad51 filaments will allow us to develop new therapeutic approaches.
Drug therapy for the management of radiation-induced hematopoietic and gastrointestinal syndromes
Nuclear technology is widely used in industry, army and medicine (diagnosis, radiotherapy and conditioning for transplants). Circumstances in which high-dose radiation exposure occurs can result in a considerable number of injuries and deaths in the absence of therapeutic intervention. These circumstances may include terrorism, accidents caused by nuclear reactor malfunctions, or radiotherapy accidents involving ionising radiation (IR) overdose. There are also medical cases of high-dose irradiation for the purpose of conditioning the patient for transplantation to treat certain diseases (acquired bone marrow failure, acute myeloblastic leukemia (AML) or hereditary aplastic anemia).
Exposure to high levels of radiation can quickly lead to acute radiation syndrome (ARS), which mainly affects hematological (blood, bone marrow) and gastrointestinal tissues in the hours, days and weeks that follow.
Hematopoietic syndrome (HS) is a major component of ARS. It develops after total body irradiation (TBI) at doses > 1 Gy and is characterized by partial or total destruction of bone marrow stem cells and their environment. The therapeutic management of HS is based on medical treatments using growth factors to stimulate residual hematopoiesis, but these may prove ineffective in cases of severe bone marrow damage. Hematopoietic stem cell transplantation is then the best treatment, but it is invasive, not always feasible due to a lack of donors, and its success rate remains extremely low, particularly due to severe side effects (risk of graft-versus-host disease).
Gastrointestinal syndrome (GIS) develops after a dose > 10 Gy (whole body or localized). It is characterized by weight loss, diarrhea and increased susceptibility to developing bacterial infections leading to septicemia. Death occurs within 5 to 12 days after irradiation. Current management is based solely on symptomatic treatments (antibiotics, anti-diarrhea drugs, anti-emetics).
It is therefore essential to develop new therapeutic methods to treat severely irradiated patients as quickly as possible after radiation exposure and with minimal side effects.
In this project, we propose to develop, through industrial and clinical collaborations, new drug therapies involving the administration of specific molecules to be tested in order to improve hematopoietic and/or intestinal recovery after irradiation.