Description du projet DEENESFRITPL La technologie unicellulaire permet de définir les sources de la synthèse de novo des nucléotides La synthèse de novo (SDN) des nucléotides est essentielle à la prolifération cellulaire, et sa perturbation est préjudiciable aux cellules cancéreuses qui se multiplient rapidement. La thérapie anti‑nucléotide a été l’une des premières approches pour traiter le cancer, mais la SDN peut être contournée par l’absorption de nucléotides extracellulaires ou par les voies de recyclage, ce qui limite l’efficacité de la thérapie. Les sources cellulaires de nucléotides dans les tissus normaux et les tumeurs in vivo n’ont pas encore été correctement caractérisées; il s’agit du principal objectif du projet MetaCross, financé par l’UE, outre la compréhension des adaptations au blocage de la SDN dans le cancer. La recherche impliquera une approche intégrative in vivo employant la technologie unicellulaire combinée à l’analyse omique unicellulaire, à la bioinformatique avancée et à des modèles murins de pointe. Afficher les objectifs du projet Masquer les objectifs du projet Objectif DNA synthesis is essential for cell proliferation. Nucleotides, the basic building blocks of nucleic acids, are made by nucleotide de novo synthesis (DNS), and DNS disruption is detrimental to rapidly proliferating cancer cells. Established >70 years ago, anti-nucleotide therapy was one of the first approaches to treat cancer, but it suffers high rate of resistance and relapse. DNS can be bypassed by an uptake of extracellular nucleotides or by recycling in salvage pathways, possibly a reason for limited efficacy of anti-nucleotide therapy. To date, the cellular sources of nucleotides in normal tissue and in tumors in vivo remain poorly characterized. The central goal of this project is to define these nucleotide sources, understand the intercellular metabolic crosstalk of nucleotides in tumors, and characterize the adaptations to DNS blockade in cancer and stromal cells. To reach these goals, I will use the totally new perspective brought by the single cell technology and combine my expertise in single cell omics and metabolism with the state-of-the-art mouse models and advanced bioinformatics available at the host institute. I propose an integrative in vivo approach using single cell RNA-sequencing, which in combination with genetic interventions will allow me to resolve dynamic expression profiles of individual cell types. I will use inducible mouse models to selectively disable DNS in the stroma (lungs of a host animal) and in cancer cells (orthotopic tumors from syngeneic DNS-deficient lung cancer cells) to generate tumors fully relying on nucleotides from internal or external sources, respectively. In parallel, I will perform in vivo CRISPR screen to identify genes whose lack represents a targetable metabolic dependency of DNS-disabled cancer cells. This innovative approach will shed novel insights into organization of tumor metabolic homeostasis and identify new targets with the potential to make major breakthrough in anti-nucleotide intervention in cancer. Champ scientifique natural sciencesbiological sciencesbiochemistrybiomoleculesnucleic acidsmedical and health sciencesclinical medicineoncologylung cancernatural sciencesbiological sciencesgeneticsnucleotidesmedical and health sciencesmedical biotechnologycells technologiesmedical and health sciencesbasic medicinephysiologyhomeostasis Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Thème(s) MSCA-IF-2020 - Individual Fellowships Appel à propositions H2020-MSCA-IF-2020 Voir d’autres projets de cet appel Régime de financement MSCA-IF-EF-ST - Standard EF Coordinateur BIOTECHNOLOGICKY USTAV AV CR VVI Contribution nette de l'UE € 156 980,64 Adresse PRUMYSLOVA 595 252 50 Vestec Tchéquie Voir sur la carte Région Česko Střední Čechy Středočeský kraj Type d’activité Other Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 156 980,64
