Descripción del proyecto
El endotelio tumoral como fuente de pirimidinas para las células cancerosas
La interrupción de la síntesis «de novo» de pirimidina (PDNS, por sus siglas en inglés) bloquea la proliferación celular. Las células cancerosas obtienen pirimidinas a través de la PDNS o de otras fuentes, y es probable que la inhibición de dicha síntesis en las células cancerosas sea eludida por las pirimidinas del entorno tumoral o de la circulación sistémica. El metabolismo de las células endoteliales (CE o EC, por sus siglas en inglés) se reconfigura en los tumores y produce un aumento regulado de la PDNS. En el proyecto EC-InterCom, financiado con fondos europeos, se pretende descubrir si la PDNS de las CE puede proporcionar directamente pirimidinas a las células cancerosas o si apoya a los tumores indirectamente, al estimular la angiogénesis. El objetivo del estudio es identificar la comunicación metabólica de las CE con otras células cancerosas y establecer nuevas dianas metabólicas en las CE para mejorar la eficacia de los inhibidores de la PDNS «in vivo».
Objetivo
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.
Ámbito científico
Programa(s)
Convocatoria de propuestas
HORIZON-WIDERA-2022-TALENTS-02
Consulte otros proyectos de esta convocatoriaRégimen de financiación
HORIZON-AG-UN - HORIZON Unit GrantCoordinador
252 50 Vestec
Chequia