DEGS1-mTORC1-driven lipid metabolic reprogramming fuels rhabdomyosarcoma progression and unveils a therapeutic vulnerability
Menée à l'aide de lignées cellulaires, de modèles murins et de drosophiles, cette étude met en évidence un mécanisme par lequel la modification du métabolisme lipidique induite par la voie de signalisation impliquant la désaturase DEGS1 et le complexe protéique mTORC1 favorise la progression du rhabdomyosarcome, puis démontre que l'inhibition simultanée de DEGS1 et mTORC1 supprime de façon synergique la croissance tumorale et le processus métastatique
Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children and adolescents, is a malignant tumor of skeletal muscle histogenesis that remains one of the most difficult pediatric cancers to cure. Here, we identify ifc, the Drosophila orthologue of DEGS1, as a key regulator of muscle stem cells (MuSCs). Ifc/DEGS1 encodes a sphingolipid desaturase that converts dihydroceramide to ceramide during ceramide biosynthesis. In Drosophila, ifc overexpression expands MuSC populations and suppresses differentiation, mirroring RMS like properties. Consistently, DEGS1 is upregulated in RMS cells, where it drives lipid droplet biogenesis and activates mTORC1 signaling to inhibit lipophagy, leading to aberrant lipid droplet accumulation. This metabolic rewiring positions lipid droplets, which have been largely overlooked in RMS biology, as central hubs that promote proliferation, suppress differentiation, and enhance metastatic potential, thereby driving RMS progression. Importantly, dual pharmacologic inhibition of DEGS1 and mTORC1 synergistically suppresses tumor growth and metastasis, revealing a lipid droplet–dependent vulnerability in RMS. Together, our findings establish a mechanistic link between sphingolipid metabolism, mTORC1-mediated regulation of lipophagy, and tumor aggressiveness, highlighting lipid droplet metabolism as a tractable therapeutic target in RMS.
Nature Communications , article en libre accès, 2026