Development of synovial sarcoma organoids exhibiting ferroptosis resistance despite low malic enzyme 1 expression

Abstract

Abstract Although several studies have investigated synovial sarcoma using established cell lines and mouse models, effective treatments remain limited. We treated five patients with synovial sarcoma at our institute between 2022 and 2023, and resected tumor specimens were cultured using a modified air–liquid interface organoid method. After serial passaging and xenografting into NOD-scid IL2Rgnull (NSG) mice, patient-derived organoid lines were successfully established in three of five cases. These organoids exhibited stable propagation, tumorigenicity, and retained histological and genetic features of the original tumors, including SS18–SSX fusion confirmed by polymerase chain reaction and Sanger sequencing. We then evaluated the organoids’ response to a ferroptosis-inducing agent previously reported to be effective in synovial sarcoma. Despite low malic enzyme 1 ( ME1 ) expression, which has been associated with ferroptosis sensitivity, the established organoids were resistant to treatment. This unexpected result suggests additional mechanisms of resistance and highlights the complexity of ferroptosis regulation in synovial sarcoma. Our findings demonstrate the feasibility of establishing synovial sarcoma organoids using a modified culture method and suggest their potential as preclinical models for drug screening and mechanistic studies. These models provide a valuable resource for the development of novel therapeutic strategies for this rare and aggressive tumor.