Projektbeschreibung
Mit Einzelzelltechnologie Quellen der Nukleotid-De-novo-Synthese bestimmen
Für die Zellproliferation ist die Nukleotid-De-novo-Synthese unbedingt notwendig. Wird sie unterbrochen, wird die schnelle Vermehrung von Krebszellen gebremst. Die Anti-Nukleotid-Therapie war einer der ersten Ansätze der Behandlung von Krebs, jedoch kann die De-novo-Synthese durch die Aufnahme extrazellulärer Nukleotide oder über Recyclingwege umgangen werden, was die Wirksamkeit der Therapie beschränkt. Zelluläre Nukleotidquellen in normalem Gewebe und in Tumoren des lebenden Organismus sind bisher noch nicht ausreichend erforscht worden. Hierin besteht das Hauptziel des EU-finanzierten Projekts MetaCross. Außerdem geht es um das Verständnis der Anpassungen an die Blockade der De-novo-Synthese bei Krebs. Die Forschungsarbeiten umfassen einen integrativen In-vivo-Ansatz, bei dem Einzelzelltechnologie mit Einzelzell-Omik-Analyse, moderner Bioinformatik und Mausmodellen gemäß neuestem Stand der Technik kombiniert wird.
Ziel
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.
Wissenschaftliches Gebiet
- natural sciencesbiological sciencesbiochemistrybiomoleculesnucleic acids
- medical and health sciencesclinical medicineoncologylung cancer
- natural sciencesbiological sciencesgeneticsnucleotides
- medical and health sciencesmedical biotechnologycells technologies
- medical and health sciencesbasic medicinephysiologyhomeostasis
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Aufforderung zur Vorschlagseinreichung
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Koordinator
252 50 Vestec
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