Intercellular trading in nucleotide metabolism: an emerging target

Introduction

Anticancer therapy is over 70 years old, and nucleotides are the oldest target in cancer treatment. Despite its long history, this treatment suffers from high rates of resistance and toxicity. What are the reasons?

Mechanisms of Resistance

A cell can gain nucleotides via de novo synthesis (DNS) or from salvage pathways. DNS inhibition can be bypassed by nucleotides produced by surrounding cells or distant organs, causing resistance.

Limitations of Traditional Studies

Cancer cells were traditionally studied in isolation, with bulk techniques precluding the identification of cell type-specific targets, which causes toxicity. To date, the cellular sources of nucleotides in healthy and tumor tissues are poorly characterized.

Hypothesis

Can the complexity of metabolic crosstalk in tissues be captured by traditional means? I hypothesize that cancer and stromal cells differ in how they utilize nucleic acid building blocks from external and internal sources.

Research Objectives

A single-cell resolution is needed to disentangle their interactions, and inhibition of both DNS and cancer-specific salvage is required for a successful blockade. I aim to:

1. Define the nucleotide sources in healthy tissues and tumors.
2. Characterize their adaptations to DNS blockade to uncover the network of metabolic interactions in tissues.
3. Find effective and specific combinations of targets.

Methodology

To reach this goal, I will use a unique combination of single-cell multi-omics and tailored mouse models, an expertise and tools that I took the lead to set up.

Experimental Design

I will selectively disable DNS in the stroma (host mouse) and in cancer cells (syngeneic lung tumors) to generate tumors dependent on internally or externally produced nucleotides.

Integrative Approach

In an integrative approach using spatial and single-cell transcriptomics & metabolomics in situ, and functional genetic screens, I will search for targetable metabolic vulnerabilities of DNS-disabled cancer cells.

Conclusion

This innovative research opens the path to understanding the organization of tissue metabolic homeostasis for new personalized metabolism-based anticancer medicine.