Periodic Reporting for period 1 - InterMet (Intercellular trading in nucleotide metabolism: an emerging target)
Reporting period: 2022-03-01 to 2024-08-31
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.
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.
We developed unique mouse and cellular models that enable us to dissect the utilization of de novo synthesized and salvaged nucleotides at the level of organism (whole-body or in endothelial cells) or specifically in cancer cells. Using these models, we uncovered an unknown metabolic role of tumor endothelial cells in regulating tumor growth.
We are investigating the extracellular adaptations that enable cancer cells with a blockade of de novo pyrimidine synthesis to restart tumor growth.
We are investigating the extracellular adaptations that enable cancer cells with a blockade of de novo pyrimidine synthesis to restart tumor growth.
We identified a new potential mechanism of resistance to antimetabolites, linked to metabolic function of tumor endothelial cells. This discovery has a potential to guide future, more efficient, anti-cancer strategies.
We are developing a compound as a potential novel anti-cancer treatment targeted at intercellular metabolic communication. Currently, we are in the process of patenting. To maximize the chances for translation, we plan to perform further experiments to document the efficacy, utility, and mechanism of action of this compound. These experiments will uncover new basic biology and pave the way for further development towards a new therapeutic.
We are developing a compound as a potential novel anti-cancer treatment targeted at intercellular metabolic communication. Currently, we are in the process of patenting. To maximize the chances for translation, we plan to perform further experiments to document the efficacy, utility, and mechanism of action of this compound. These experiments will uncover new basic biology and pave the way for further development towards a new therapeutic.