Disrupting the lipid-ETV6 axis: A therapeutic vulnerability in Ewing sarcoma

Ewing sarcoma is a transcriptionally driven pediatric cancer with few targetable dependencies. Through a gain-of-function metabolic screen, we discovered that Ewing sarcoma cells exhibit lineage-specific hypersensitivity to activation of glycerophospholipid metabolism. Mechanistic studies revealed that phosphatidic acid (PA), a central lipid signaling molecule, directly binds to the transcriptional repressor ETV6, an essential and selective dependency in Ewing sarcoma. PA binding disrupts ETV6 oligomerization and chromatin occupancy, leading to de-repression of its target genes. We further mapped this interaction to a unique five-amino acid motif in the ETV6 ETS domain and generated lipid-insensitive mutants that retain DNA binding but resist PA-induced inactivation. CRISPR activation of endogenous PA-producing enzymes phenocopied the effects of exogenous PA, supporting a direct role for lipid signaling in modulating ETV6 function and tumor cell viability. These findings define a previously unrecognized lipid-sensitive transcriptional state in Ewing sarcoma and reveal the ETV6-PA axis as a novel therapeutic target.