Chemical biology approaches to rare earth toxicology in Humans
Recent technological developments have expanded and intensified the use of lanthanides in domains as diverse as renewable energy, computing, and medicine. Increasing usage of these metals raises the question of their impact on the environment and human health. However, the potential toxicity of these metal ions, and its underlying molecular mechanisms, are still little known and rarely investigated in human cell models. The goal of the PhD will be to investigate the human cells response to exposure to Ln ions, and to systematically identify the proteins involved in this response, using a set of chemical and biological tools. In particular, we want to address the following questions: which protein networks are activated or deactivated following Ln exposure? Do Ln ions affect phosphorylation of proteins? Which proteins are directly interacting with Ln ions? will thus decipher what are the key biological interactors of lanthanides, their roles in living systems and the features that enable efficient binding to metals. We expect that our findings will give insights into the toxicology of those elements and inform environmental and occupational safety policies. On the longer term, new bio-inspired strategies for their extraction, recycling, decorporation and remediation will arise from the molecular understanding of metal-life interactions, enabling a well thought-out usage of these elements to support the environmental and numerical transitions.s
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.).
The combined effects of hypoxia and matrix stiffness on the pathophysiology of pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal lung disease characterized by excessive extracellular matrix (ECM) deposition, increased tissue stiffness, and localized hypoxia. These alterations disrupt cell–cell interactions within the alveolo-capillary barrier and drive fibrotic progression. This project aims to investigate, under controlled in vitro conditions, the combined impact of mechanical stiffness and hypoxic stress on the fate and phenotype of pulmonary cell types and their intercellular communication. To achieve this, biomimetic polyacrylamide hydrogels with tunable stiffness and specific ECM protein coatings will be developed to support the co-culture of alveolar epithelial cells, endothelial cells, fibroblasts, and macrophages. Cellular responses will be assessed through proteomics, imaging, and secretome profiling. The goal is to identify key mechano- and chemo-dependent pro-fibrotic factors, providing new insights into IPF pathogenesis and opening avenues for targeted therapeutic strategies and lung tissue regeneration.
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.
Magneto-mechanical stimulation for the selective destruction of pancreatic cancer cells while sparing healthy cells
A novel approach for selectively destroying cancer cells is being developed through a collaboration between the BIOMICS biology laboratory and the SPINTEC magnetism laboratory, both part of the IRIG Institute. This method employs magnetic particles dispersed among cancer cells, which are set into low-frequency vibration (1–20 Hz) by an applied rotating magnetic field. The resulting mechanical stress induces controlled cell death (apoptosis) in the targeted cells.
The effect has been demonstrated in vitro across various cancer cell types—including glioma, pancreatic, and renal cells—in 2D cultures, as well as in 3D pancreatic cancer spheroids (tumoroids) and healthy pancreatic organoids. These 3D models, which more closely mimic the structure and organization of real biological tissues, facilitate the transition to in vivo studies and reduce reliance on animal models. Preliminary findings indicate that pancreatic cancer cells exhibit a higher affinity for magnetic particles and are more sensitive to mechanical stress than healthy cells, enabling selective destruction of cancer cells while sparing healthy tissue.
The next phase will involve confirming this specificity in mixed spheroids (containing both cancerous and healthy cells), statistically quantifying the results, and elucidating the mechanobiological mechanisms underlying cell death. These promising findings pave the way for an innovative biomedical approach to cancer treatment.
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.
Endothelial-fibroblast interactions in diabetic foot ulcer: deciphering the intercellular communication responsible for the chronic wound persistence
Diabetic foot ulcer (DFU), a severe complication of diabetes affecting approximately 18.6 million people worldwide each year, is associated with high rates of amputation and mortality. Like other chronic wounds, DFUs exhibit impaired healing due to a dysregulated cascade of cellular signalling and behavioural events that normally ensure rapid closure of the skin barrier. Among the key cellular players, fibroblasts and endothelial cells are central to the proliferative and remodelling phases of wound repair – processes that are notably dysfunctional in chronic wounds. Although endothelial-fibroblast crosstalk is recognized as an essential driver of normal skin healing, the specific mechanisms governing their interaction in DFU is poorly understood.
The main objective of this PhD project is to decipher the intercellular communication between endothelial cells and fibroblasts that underlies the chronicity of DFU. Particular attention will be devoted to extracellular vesicle-associated microRNAs (miRNAs), which are pivotal regulators of intercellular communication through modulation of gene expression in recipient cells. By characterizing the repertoire of pro- and anti-healing miRNAs exchanged between endothelial cells and fibroblasts, this project seeks to uncover novel molecular targets and therapeutic strategies to promote wound repair in diabetic foot ulcers.
Stabilization and pharmacological characterization of engineered ß-Amyloid oligomers for diagnostic and therapeutic innovation in Alzheimer’s disease
Alzheimer’s disease (AD) is the leading cause of dementia worldwide, yet its molecular mechanisms remain poorly understood. Numerous studies have shown that soluble oligomers of the amyloid-ß peptide (Aß1-42) are the earliest and most toxic forms in the amyloid cascade, responsible for initial neuronal damage prior to plaque formation. However, their intrinsic instability makes them difficult to study.
This project aims to design stable analogues of the Aß peptide capable of organizing into well-defined oligomeric forms, particularly tetramers and octamers. These species will be structurally and pharmacologically characterized to better understand their neurotoxic effects and interactions with neuronal membranes.
Fluorescent probes developed in the laboratory will enable the tracking of these species in cellular models and in vivo, through a collaboration with Dr. Nadja Van Camp (MIRCen).
The expected results will help identify the Aß forms truly responsible for neurodegeneration, pave the way for more selective therapeutic strategies, and support the development of innovative approaches for the early diagnosis of Alzheimer’s disease.
Development of photo-printed interferometric biosensors on multi-core optical fibers for molecular diagnostics
Optical fibers are minimally invasive devices commonly used in medicine for in vivo tissue imaging by endoscopy. However, at present, they only provide images and no molecular information about the tissues observed. The proposed thesis is part of a project aimed at giving optical fibers the ability to perform molecular recognition in order to develop innovative biosensors capable of performing real-time, remote, in situ, and multiplexed molecular analysis. Such a tool could lead to significant advances in the medical field, particularly in the study of brain pathologies, where knowledge of the tumor environment, which is difficult to access using conventional biopsies, is essential.
The proposed approach is based on 2-photon polymerization printing of interferometric structures at the end of each core of a multifiber assembly. The detection principle is based on the interference occurring in these structures and their modification by the adsorption of biological molecules. Each fiber in the assembly will act as an individual sensor, and measuring the intensity of the light reflected at the functionalized end will provide information about the biological interactions occurring on that surface. By modeling the interference phenomenon, we determined parameters to optimize the shape and sensitivity of interferometric structures (PTC InSiBio 2024-2025). These results enabled the printing and characterization of the sensitivity of interferometric structures on single-core fibers. The objectives of the thesis are to continue this optical characterization on new samples and to develop original photochemical functionalization methods in order to graft several biological probes onto the surface of the fiber assemblies. This multi-functionalization will enable multiplexed detection, which is essential for future medical applications. Depending on the progress of the thesis, the biosensors will be validated through the detection of biological targets in increasingly complex environments, up to and including a brain tissue model.
Development of an integrated solid state nanopore analysis system
The identification of biological material (DNA, RNA, proteins,…) is generally done thanks to cumbersome lab equipment and/or rely on ultra-specific and proprietary sensitive reagents. We aim to develop a new platform based on the solid-state nanopore technology which could produce label-free results on field.
One way to pierce a nanopore in an ultra-fine dielectric membrane is to use an electron beam. An ion current is obtained when placing this pierced membrane in-between two insulated reservoirs filled with electrolytes and applying a low voltage. A particle going through the pore modifies this ionic current giving us information on its size, charge or conformation.
For this technique to yield the best results we need control over each bit of the platform: the dielectric assembly and nanopore within; the high speed and precision electronic apparatus to measure ionic current; the fluidic integration and even the algorithm responsible for deciphering the current trace. Starting from the simplest setup possible, the PhD candidate will have to push forward every aspect of this ambitious project, aiming for protein sequencing, relying on the multiple expertise of the Leti and the Lambe laboratory.