Descrizione del progetto
La tecnologia a singola cellula contribuisce a definire le fonti di sintesi de novo dei nucleotidi
La sintesi de novo dei nucleotidi è essenziale per la proliferazione cellulare e la sua alterazione è dannosa per le cellule tumorali che si moltiplicano rapidamente. La terapia antinucleotidica è stata uno dei primi approcci al trattamento del cancro, ma la sintesi de novo dei nucleotidi può essere aggirata dall’assorbimento di nucleotidi extracellulari o attraverso percorsi di riciclo, limitando l’efficacia della terapia. Le fonti cellulari di nucleotidi nei tessuti normali e nei tumori in vivo non sono ancora state adeguatamente caratterizzate ed è proprio l’obiettivo principale del progetto MetaCross, finanziato dall’UE, oltre alla comprensione degli adattamenti al blocco della sintesi de novo dei nucleotidi nel cancro. La ricerca comporterà un approccio integrativo in vivo utilizzando la tecnologia a singola cellula combinata ad analisi omica a singola cellula, bioinformatica avanzata e modelli murini all’avanguardia.
Obiettivo
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.
Campo scientifico
- natural sciencesbiological sciencesbiochemistrybiomoleculesnucleic acids
- medical and health sciencesclinical medicineoncologylung cancer
- natural sciencesbiological sciencesgeneticsnucleotides
- medical and health sciencesmedical biotechnologycells technologies
- medical and health sciencesbasic medicinephysiologyhomeostasis
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
252 50 Vestec
Cechia