Bulk RNA sequencing of DEGS1 overexpression in myoblast and rhabdomyosarcoma cell lines.

ABSTRACT: 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 expanded MuSC populations and suppressed 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 novel metabolic rewiring positions lipid droplets—long overlooked in RMS biology—as central hubs that enhance proliferation, suppress differentiation, and increase metastatic potential, thereby accelerating RMS progression. Importantly, dual pharmacologic inhibition of DEGS1 and mTORC1 synergistically suppresses tumor growth and metastasis, revealing a previously unappreciated 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 novel and tractable therapeutic target in RMS.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE331021 | GEO | 2026/08/24

REPOSITORIES: GEO