Data-Gouv-ML/pcri-actions-marie-curie-participations-et-projets-laureats huggingface dataset:
Projet DNA-MolScaff (Horizon Europe, appel à projets 2023)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : SIGNED

Mitochondrial cristae are functional dynamic compartments containing the respiratory chain complexes where oxidative phosphorylation occurs. They are separated from the inner boundary membrane by highly curved and tightly regulated membrane compartments called crista junctions (CJs). A key multi-protein complex, mitochondrial contact site and cristae organizing system (MICOS), is enriched in CJs and plays a central role in modulating the architecture and function of CJs. Recently, a MICOS subcomplex built by the Mic60-Mic19 tetramer was proposed to traverse the CJ like a molecular strut and hypothesized to act as a diffusion barrier for metabolites and proteins between the inner mitochondrial membrane and the cristae lumen. However, the exact location of this MICOS subcomplex in CJs, its proposed diffusion barrier function and its detailed role in modulating CJ architecture are not clear. Here, I propose to fabricate a CJ mimic to reconstitute the Mic60-Mic19 tetramer into an octagonal donut-shaped DNA origami scaffold. The surface of the DNA origami will be coated with a lipid monolayer, enabling stabilization of the reconstituted complex, and facilitating structural studies using cryo-electron microscopy (cryo-EM). Subsequently, the role of Mic60-Mic19 complex and its intrinsically disordered regions as a diffusion barrier will be probed by incorporating the CJ mimics onto the surface of the liposomes. These efforts will reveal the structure of the Mic60-Mic19 subcomplex in a near-native environment and its role in the transport of proteins and metabolites, thereby providing an in-depth understanding of its cellular function. The realization of membrane-coated DNA origami molecular scaffolds as platforms for reconstituting proteins may pave the way for nano-tools that are made from DNA for structural and functional exploration of other challenging membrane and membrane-interacting proteins, which could yield valuable insights into key biological processes.

Mots clés : dna origami, cryo em, mitochondrial cristae junctions, micos, dna aptamers, dna protein interactions, diffusion experiments

Participants :
- Max Delbrück Center (Allemagne) — Coordinator, beneficiary, Recherche, subvention : 173847.36 €
Projet HERSTRUCT (Horizon Europe, appel à projets 2024)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : SIGNED

The HERSTRUCT project seeks to uncover the structural and functional mechanisms of HER2 and HER3, two proteins that are pivotal in driving cancer progression, particularly in aggressive breast and lung cancers. HER2 is often overexpressed in these types of cancers, leading to unchecked cell proliferation, while HER3 collaborates with HER2 to intensify the signaling pathways that sustain tumor growth and survival. Despite extensive research, the precise nature of the HER2-HER3 interaction in cancer cells, especially within their native membrane environment, remains elusive and closely linked to cancer resistance to therapies.  Leveraging cutting-edge cryo-electron tomography (cryo-ET), the HERSTRUCT project aims to produce the first 3D structural view of the full-length HER2-HER3 complex in its natural membrane environment. This approach will provide unprecedented insights into how these two proteins function together at the molecular level. Functional assays will investigate how HER2 and HER3 trigger cancer-promoting signals, while mass spectrometry will identify additional molecules interacting with the complex, offering a complete view of their role in cancer progression and therapy resistance.  In collaboration with leading research institutes, HERSTRUCT will explore how these structural insights can be applied to develop cancer therapies specifically targeting HER2-HER3 interactions. This effort not only fills a key gap in cancer research but also has the potential to lead to more personalized and effective treatments, particularly for HER2-positive cancers, where drug resistance is a challenge.  The fellowship will provide me with cutting-edge expertise in cryo-ET and advanced data analysis, strengthening my skills and preparing me for a leadership role in cancer research. This project addresses a critical challenge in cancer biology and offers the potential to improve treatment outcomes for patients with HER2-driven cancers.

Mots clés : membrane proteins, protein complexes, cryo electron tomography, drug resistance, mass spectrometry

Participants :
- Max Delbrück Center (Allemagne) — Coordinator, beneficiary, Recherche, subvention : 202125.12 €
Projet EVO-PDAC (Horizon Europe, appel à projets 2023)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : SIGNED

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, a disease with a dismal prognosis. PDAC has an especially high tendency of quickly metastasizing and becoming resistant to therapy, and the mechanisms by which this occurs are largely unknown. Recent evidence suggests that saltatory or “burst-like” evolution mediated by complex genomic rearrangements (CGRs) may be especially relevant in PDAC, altering multiple cancer genes in a single event. However, quantifying CGRs requires specialized techniques (such as Strand-Seq), and therefore the relative importance of CGRs, simple structural variants, and point mutations in PDAC evolution remains unclear. In this project, we will use a genetically engineered mouse model (GEMM) that develops de novo PDAC to longitudinally track PDAC evolution by single-cell and spatial multi-omic methods, using Strand-Seq to accurately detect CGRs. Thus, we aim to create longitudinal single-cell and spatial multi-omic atlases of PDAC at three key evolutionary steps: pre-cancer, therapy-naive PDAC, and post-therapy PDAC. In addition, we will compare our atlases to human PDAC data from the Spatial And Temporal Resolution of Intratumoral Heterogeneity in 3 hard-to-treat Cancers (SATURN3) Consortium. In this way, we will model PDAC evolution at various time points, quantifying the relative importance of gradual vs saltatory evolution and determining how evolvability changes over time. Moreover, we will infer the role of selective pressures from the tumor microenvironment (e.g., immune cells and cancer-associated fibroblasts) in shaping PDAC evolution. Finally, we will explore how all these factors interact with the high intratumoral heterogeneity observed in PDAC. Overall, this project will answer long-standing questions about the evolutionary dynamics of PDAC.

Mots clés : single cell multi omics spatial multi omics cancer evolution pancreatic cancer structural variation

Participants :
- Laboratoire européen de biologie moléculaire (Allemagne) — Coordinator, beneficiary, Recherche, subvention : 173847.36 €
Projet DictyDefense (Horizon Europe, appel à projets 2023)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : SIGNED

Bacteria are the backbone of natural communities. A single gram of soil may contain up to 10 billion cells. Two types of bacterial predators are also abundant: protozoa, single-celled eukaryotes that phagocytize bacteria, and bacteriophages (phages), viruses that only infect bacteria. Each day, up to 20% of the global bacterial population is killed by these two predators. This puts pressure on bacteria to adapt defense strategies, but also on each predator to out-compete the other. However, the interplay between bacteria, phages, and protozoa is rarely studied.  Certain phages can integrate into bacterial genomes, becoming prophages, and encode beneficial traits for host fitness, like protection from other phages. My hypothesis is that prophages encode defense mechanisms that may interfere with protozoan predation and protect the bacterial host, thereby indirectly benefiting the prophage. To investigate this, I will develop a high-throughput quantitative fluorescence predation assay, using the amoeba Dictyostelium discoideum as the model protozoan. Changes in abundance of fluorescently tagged bacteria with and without defense functions will report the strength of predation defense in a large bacterial isolate panel harbouring thousands of prophages. The assay will be scaled up with robotics platforms. Gain of function screens will be used to link defense phenotype with individual genes. After prioritizing the defense hits for novel biology, the major stages of predation that are inhibited can be observed by real time tracking of interactions between fluorescently tagged cells. Biochemical and genetic follow-ups will pinpoint the exact mechanisms of defense. Proteomic, transcriptomic, and lipidomic methods will assess changes in bacterial and protozoan physiology. Overall, this proposal addresses an important blind-spot in the interactions of bacteria, protozoa, and phages and will reveal new aspects on how predatory interactions shape microbial ecosystems.

Mots clés : bacteriophages amoeba protozoa genetic tools

Participants :
- Laboratoire européen de biologie moléculaire (Allemagne) — Coordinator, beneficiary, Recherche, subvention : 189687.36 €
Projet MTOControl (Horizon Europe, appel à projets 2022)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Microtubule-organizing centers (MTOCs) are key eukaryotic structures for microtubule nucleation and organization. Many MTOCs contain centrioles, organelles with two critical functions. i) In mitosis, they localize to the pole of the mitotic spindle aiding its organization. ii) After cell division, centrioles are repurposed as basal bodies at the plasma membrane where they are essential for cilia/flagella formation. Defects in centriole/basal body (CBB) repurposing can have devastating consequences and lead e.g. to infertility in human sperm. CBB functions correlate with subcellular localization, but is the spatiotemporal control required for this organelle to fulfill two distinct functions? How did the ancestral CBB evolve these functions? And why are different MTOCs not present simultaneously in a cell? To tackle these questions, I will first analyze and compare CBB repurposing strategies during the cell cycle of the green alga Chlamydomonas rheinhardtii with those in the complex life cycle of the acellular slime mold Physarum polycephalum, two evolutionary distant eukaryotes. To do so, I will develop and apply a correlative microscopy workflow in which time-lapse imaging of cells is followed by cryo-fixation and expansion microscopy (Cryo-ExM) combined with Stimulated Emission Depletion (STED). Using transient overexpression and laser ablation, I will interfere with spatial and temporal control of CBB repurposing to elucidate the role of subcellular location of this bifunctional organelle. Further, I will study how cells cope with several different MTOCs at a time, likely competing for tubulin. This project will provide a novel, high-end correlative live-cell and super-resolution imaging pipeline, which can be easily adapted for various species and cellular structures. Understanding the different strategies of CBB repurposing that evolved will have broad implications as a basis to understand CBB defects in the human cell cycle and during spermatogenesis.

Mots clés : microtubule organizing center, centriole, basal body, centrosome, flagella, cilia, cell cycle, division, open mitosis, closed mitosis

Participants :
- Laboratoire européen de biologie moléculaire (Allemagne) — Coordinator, beneficiary, Recherche, subvention : 173847.36 €
Projet PaedsSeq (Horizon Europe, appel à projets 2022)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Paediatric cancer is the leading cause of death in children post infancy in the Western world. The integration of high-throughput molecular profiling is now urgently needed to guide clinical decision-making and treatment stratification. However, access to adequate tumour material for genomic profiling remains highly challenging, particularly in children with refractory cancers, due to sampling difficulties and small sample volumes. The analysis of cell-free DNA (cfDNA) from liquid biopsies for the detection of circulating tumour DNA (ctDNA) could offer a powerful, minimally invasive alternative to tumour profiling, thus circumventing sampling limitations. However, current ctDNA approaches have limited specificity and sensitivity, and their clinical implementation is hindered by poor scalability and high costs associated with conventional sequencing technologies. In contrast, emerging nanopore sequencing platforms have faster turnaround times, are more affordable and significantly smaller than conventional sequencers, making them easy to deploy and implement in healthcare settings. However, their utility for cfDNA analyses remains largely unexplored. Here, using available data and liquid biopsy samples from ~500 children with cancer, I will develop computational tools for the detailed analysis of cfDNA nanopore sequencing data. By harnessing nanopore’s ability to sequence native DNA, thus allowing the detection of mutational DNA alterations and epigenetic modifications from the same assay, I will: (a) establish highly sensitive and specific approaches for the detection and molecular profiling of ctDNA, (b) develop methylation-based disease classifiers for accurate diagnosis and treatment stratification, and (c) evaluate the clinical utility of cfDNA nanopore sequencing to monitor treatment response and detect cancer relapse. The clinical implementation of these approaches could therefore significantly improve disease management and outcomes for children with cancer.

Mots clés : cancer genomics, liquid biopsies, cell free dna, paediatric cancer, nanopore sequencing, early detection, copy number aberrations, dna methylation, disease classification

Participants :
- Université de Birmingham (Royaume-Uni) — Partner, associated partner, Enseignement supérieur ou secondaire, subvention : 0.0 €
- Laboratoire européen de biologie moléculaire (Allemagne) — Coordinator, beneficiary, Recherche, subvention : 220908.48 €
Projet NutFLirsFA (Horizon Europe, appel à projets 2022)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : CLOSED

Metabolic reprogramming enables cells to adopt different phenotypes, providing flexibility in response to environmental stress, of particular relevance during tumour development. I recently demonstrated that the transcription factor MITF, known regulator of cell transitions in melanoma, controls the expression of the fatty acid (FA) desaturase SCD1. The MITF/SCD1 axis maintains cell differentiation, while its suppression by starvation-induced Integrative Stress Response (ISR) originates dedifferentiation and melanoma progression. Our findings support that metabolic rewiring and phenotype switching are interconnected events that govern tumour progression. As in melanoma, B-cell differentiation depends on MITF activity, FA metabolism and a dynamic modulation of ISR, but weather an interplay among these factors dictates B-cell fate is still unknown. Importantly, MITF is regulated by mTORC1/RagGTPase signalling, pathway frequently mutated in B-cell lymphomas. I hypothesize that the ISR/MITF axis and FA metabolism enable normal and pathological B cells to adapt to stress, and critically licenses switches in phenotypic identity and B-cell behaviour. Thus, I will establish if and how MITF and FA composition control B-cell transitions and impact lymphomagenesis, along with its regulation by the ISR. We propose that abnormal ISR and MITF/SCD1 deregulation corrupts B-cell differentiation process, contributing to lymphomagenesis. This proposal aims at shedding light on the interplay between nutritional signals and stress-related cellular responses that precipitate cancer cell transitions through the regulation of specific transcriptional programs controlling metabolic rewiring.

Mots clés : mitf, mit family members, isr, fatty acids, nutrients, ragc mutations, b cell, cell fate, lymphoma

Participants :
- Centre National de Recherches Oncologiques (Espagne) — Coordinator, beneficiary, Recherche, subvention : 165312.96 €
Projet CRINOVA (Horizon Europe, appel à projets 2023)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Chemistry
Statut du projet : SIGNED

Ovarian carcinoma (OC) is a leading cause of cancer deaths in postmenopausal women worldwide. Unfortunately, it is diagnosed in the advanced stages (III/IV) with five-year survival rate of 20% and poor prognosis due to lack of distinct early symptoms. The current diagnostic tools (pelvic examination and imaging techniques) often fail to detect premalignant tumors and standard biomarker (cancer antigen 125) analysis show low sensitivity and specificity. The goal of this proposal is to develop a radically innovative modality in the field of early diagnosis of ovarian cancer. I propose cutting-edge CRISPR/Cas (Clustered regularly interspaced short palindromic repeats/CRISPR associated protein) technology-based molecular diagnosis as the next generation OC screening tool.  The proposed CRINOVA project will apply the CRISPR-mediated biosensing approach for the first time combining with immunoassay to detect OC protein biomarkers (cancer antigen 125, human epididymis protein 4 and mesothelin) noninvasively in urine of early stage (I/II) OC patients through electrochemistry. The nucleic acid programmed nuclease activity of Cas effector protein will be activated upon sequence-based recognition of guiding RNA of CRISPR by a single strand DNA in the presence of biomarkers resulting in their highly specific and sensitive detection. The purpose of the project is linked to improving prognosis of OC patients, making a direct impact on enhancing their quality of life. This major objective will be achieved through a cross-disciplinary approach involving my wide experience in electrochemical biosensor development and the expertise of my supervisor on DNA nanotechnology and CRISPR-based biomolecular sensors. I have an excellent track record of scientific collaborations undertaking international mobility in different laboratories globally. The outcome of the fellowship will be crucial to boost my career in academia and to achieve a permanent position (i.e. professorship) in Europe.

Mots clés : biosensor crispr cas, protein biomarkers, ovarian cancer, paper based spes, noninvasive detection

Participants :
- Université de Rome « Tor Vergata » (Italie) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 188590.08 €
- Université de Novi Sad (Serbie) — Partner, associated partner, Enseignement supérieur ou secondaire, subvention : 0.0 €
Projet DL-I-PBraTSC (Horizon Europe, appel à projets 2023)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Information Science and Engineering
Statut du projet : SIGNED

The DL-I-PBraTSC project aims to address the significant impact of pediatric brain tumors (PBTs) as the leading cause of cancer death in children and adolescents. Artificial Intelligence (AI) technologies are increasingly being explored to assist doctors in detecting and diagnosing through clinical decision support systems (CDSS). However, They face the challenges in successfully segmenting PBTs due to the scarcity of available medical image datasets. Additionally, the lack of transparency in black-box AI models has raised concerns among doctors, hindering the adoption of AI in CDSS. To tackle these challenges, the project will develop a state-of-the-art interpretable AI-based framework to classify PBTs including tumor segmentation. DL-I-PBraTSC will identify the location of PBTs, classify of PBT types, and enable quantitative analysis of sub-region of PBT parameters helping clinicians in diagnosis, treatment planning, monitoring disease progression, and predicting patient outcomes. The project will start with collecting and preparing sufficiently large, balanced PBT medical images from secondment institution with the assistance of medical experts. An online test platform will be implemented for clinicians to use the model, gathering feedback for further validation and improvements. The non-academic placement will provide real-world clinical validation of the model's efficacy. The project findings will be shared in conferences or journals targeting both neuroscience and informatics. DL-I-PBraTSC can help healthcare providers make more informed decisions about diagnosis and treatment planning of PBTs and contribute to early detection and intervention. These can lead to better patient outcomes, improved overall healthcare delivery and public health outcomes, and reduced healthcare costs, aligning with the EU's objectives of providing ensuring the safety and well-being of its citizens and one of the Irish national research priorities areas, Health and Wellbeing.

Mots clés : explainable artificial intelligence, model interpretability, brain tumor classification, image segmentation, magnetic resonance imaging

Participants :
- Université nationale d'Irlande à Galway (Irlande) — Coordinator, beneficiary, Enseignement supérieur ou secondaire, subvention : 269418.0 €
- Université d'Ankara (Turquie) — Partner, associated partner, Enseignement supérieur ou secondaire, subvention : 0.0 €
- Children's Health Ireland at Crumlin (Irlande) — Partner, associated partner, Organismes publics (hors enseignement & recherche), subvention : 0.0 €
Projet TRICOT (Horizon Europe, appel à projets 2023)
Action : Postdoctoral Fellowships - European Fellowships
Panel : Life Sciences
Statut du projet : SIGNED

Plants evolved diverse strategies, including the production of specialized metabolites to adapt to changing environments. These specialized metabolites are often linked to glandular trichomes (GTs) density. To study GT’s biology, cultivated tomato and their wild relatives are considered ideal models, varying in GT types (I, IV, VI, VII) and associated metabolites. While type IV GTs, rich in acyl sugars (AS), persist throughout the life cycle of wild tomatoes, in cultivated varieties, they explicitly appear in early stages (especially on hypocotyl and cotyledons). AS provides resistance to various pathogens, including whiteflies, a significant threat to global tomato production. Although the role of type IV GTs and AS in adult plant resilience is understood, their regulation at the juvenile stage remains unknown. This study aims to address these knowledge gaps, employing an integrative OMICS approach in the early developmental stages of cultivated tomato and their wild relatives. While factor like plant hormone jasmonic acid (JA) is known to influence the development of type VI GTs and terpenoid metabolism, the JA-mediated regulation of type IV GTs and AS metabolism remains unidentified. The present proposal aims to tackle these crucial knowledge gaps by utilizing combinatorial forward and reverse genetics approaches. Furthermore, this project aims to explore the ecological functions of type IV GTs and AS in shaping the plant microbiome at the cotyledon stage, a yet unknown aspect of plant fate. Through an interdisciplinary approach, including genetics, transcriptomics, metabolomics, and microbiome analysis, the research aims to offer comprehensive insights into plant defense mechanisms and adaptation strategies in early developmental stages. The outcomes of this research will revolutionize our understanding of plant resilience at juvenile stages, thereby contributing to the progress of sustainable agriculture and offering new opportunities for crop improvement.

Mots clés : crop resilience, tomato, seedling development, glandular trichome, specialized metabolites, acyl sugars, hormone, jasmonates, transcriptome analysis, metabolomics, gene regulatory network, microbiome

Participants :
- Leibniz-Gemeinschaft (Allemagne) — Coordinator, beneficiary, Recherche, subvention : 189687.36 €