Pyrimidine de novo synthesis in tumor endothelium: an overlooked target?

It sounds simple: A cell cannot divide without nucleotides. Indeed, the disruption of pyrimidine de novo synthesis (PDNS) efficiently blocks proliferation of cancer cells. Yet still today, PDNS-directed anticancer treatment has not entered clinics due to the lack of efficacy. Why?

Cancer cells gain pyrimidines via PDNS or from salvage pathways, and PDNS inhibition in cancer cells can likely be bypassed by pyrimidines produced in the tumor environment or gained from the systemic circulation. Can we target this microenvironmental interaction to improve treatment efficacy? A crucial component of tumor environment are blood vessels.

Tumors stimulate their growth, angiogenesis, to gain oxygen and nutrients. Metabolism of endothelial cells (ECs), the inner vessel lining, is rewired in tumors, and tumor ECs upregulate PDNS. However, whether and how elevated PDNS in ECs supports tumorigenesis is unknown.

I hypothesize that PDNS in ECs affects tumor environment either directly by providing pyrimidines to cancer cells or indirectly by stimulating angiogenesis, making systemic resources more accessible to cancer cells.

The central goals of this project are (i) to identify the metabolic communication of ECs with other cell types in tumors, (ii) asses if endothelial PDNS promotes angiogenesis, and (iii) to seek novel metabolic targets in ECs, whose inhibition improves efficacy of PDNS inhibitors in vivo. To reach these goals, I will use an inducible mouse model to selectively disable PDNS in the endothelium.

With this unique tool available at my host institute, I will integrate a state-of-the-art multi-omics and my expertise in metabolism to disentangle the network of metabolic communication using a powerful combination of spatially resolved single cell transcriptomics, metabolomics and functional genomics.

My innovative approach will open a way for understanding the EC contribution to metabolic balance in tumors with a potential to identify new metabolic anti-cancer strategies.