PAX translocations remodel mitochondrial metabolism through altered leucine usage in rhabdomyosarcoma
Menée à l'aide de modèles murins et de xénogreffes de rhabdomyosarcome alvéolaire avec fusion du gène PAX, cette étude met en évidence un mécanisme par lequel les translocations de PAX remodèlent le métabolisme mitochondrial en modifiant l'utilisation de la leucine dans la tumeur
Alveolar rhabdomyosarcoma (ARMS) patients harboring paired-box fusion proteins (PAX3/7-FOXO1) exhibit a greater incidence of tumor relapse, metastasis, and poor survival outcome, thereby underscoring the urgent need to develop effective therapies to treat this subtype of childhood cancer. To uncover mechanisms that contribute to tumor initiation, we develop a muscle progenitor model and use epigenomic approaches to unravel genome rewiring events mediated by PAX3/7 fusion proteins. Among the key targets of PAX3/7 fusion proteins, we identify a cohort of oncogenes, fibroblast growth factor (FGF) receptors, tRNA-modifying enzymes, and genes essential for mitochondrial metabolism and protein translation, which we successfully targeted in preclinical trials. We identify leucine usage as a key factor driving the growth of aggressive PAX-fusion tumors, as limiting its bioavailability impaired oxidative phosphorylation and mitochondrial metabolism, delaying tumor progression and improving survival in vivo. Our data provide a compelling list of actionable targets and suggest promising new strategies to treat this tumor.
Cell , résumé 2024