Nucleotides are the oldest target in cancer treatment. Despite its long history, therapies that target nucleotide metabolism suffer high rates of resistance and toxicity. What are the reasons? A cell can gain nucleotides via de novo synthesis or from salvage pathways. This suggests that de novo synthesis inhibition can be bypassed by nucleotides produced by surrounding cells or distant organs, causing resistance. Cancer cells were traditionally studied in isolation in the absence of the natural environment of the tumor, using techniques precluding identification of cell type-specific treatment effects. To date, the cellular sources of nucleotides in healthy and tumor tissues are poorly characterized.
We hypothesize that cancer and stromal cells differ in how they utilize nucleic acid building blocks from external and internal sources, and mapping the intercellular trading of metabolites in tumors will point to new paths to effective and cancer-specific therapies.
The key research questions of this project are: What are the cellular sources of nucleotides in tissues? How is metabolic crosstalk organized in healthy tissue and in tumors? How individual cell types contribute to tissue metabolic homeostasis?
The project has three complementary objectives:
1. To define the cellular sources of nucleotides in healthy tissues and tumors.
2. To characterize their adaptations to nucleotide synthesis blockade.
3. To find effective and specific combination of targets for new therapeutic strategies.
We explore the consequences of nucleotide synthesis loss at single cell level using mouse and cellular models of selective nucleotide synthesis deficiency. Using methods with spatial resolution, we are investigating the intercellular interactions in tissues and tumors. We use functional genomics screens to identify genes synthetically lethal at the background of nucleotide synthesis inhibition, which will be tested as potential new targets for therapies.
This research opens the path to understanding the organization of tissue metabolic homeostasis and promises to guide new strategies for metabolism-based anticancer medicine.
