{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE332nnn/GSE332586/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE332586"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Mevalonate pathway activation in Ewing sarcoma reveals a 3D-specific synergy between statins and BCL-xL inhibition","description":"Bone sarcomas are rare and aggressive pediatric cancers with limited progress in targeted therapy development, partly due to the poor physiological relevance of conventional two-dimensional (2D) culture systems used for preclinical testing. To address this gap, we developed a standardized three-dimensional (3D) culture and drug-testing platform for Ewing sarcoma (ES) and osteosarcoma (OS) that more accurately recapitulates in vivo tumor biology. Notably, gene-expression analyses demonstrated that ES and OS spheroids transcriptionally converge toward patient tumor cell states, underscoring their physiological relevance for preclinical testing. Across 3D spheroids, bioprinted constructs, and patient-derived xenograft (PDX) cultures, we observed a consistent activation and dependency on the mevalonate pathway in ES. Leveraging this platform, we identified a selective therapeutic synergy between statins, which inhibit mevalonate pathway flux, and BCL-xL inhibitors—a vulnerability not detectable in 2D cultures. Importantly, this synergistic interaction was tumor-specific and absent in non-malignant fibroblasts, indicating a favorable therapeutic window. Together, these findings highlight the mevalonate pathway as a targetable metabolic dependency in ES and demonstrate how physiologically grounded 3D models can uncover clinically actionable treatment strategies that remain hidden in traditional 2D systems.","dates":{"publication":"2026/05/21"},"accession":"GSE332586","cross_references":{"GSM":["GSM9751080","GSM9751081","GSM9751082","GSM9751102","GSM9751103","GSM9751104","GSM9751105","GSM9751106","GSM9751107","GSM9751108","GSM9751109","GSM9751083","GSM9751084","GSM9751085","GSM9751086","GSM9751087","GSM9751088","GSM9751100","GSM9751089","GSM9751101","GSM9751090","GSM9751091","GSM9751092","GSM9751093","GSM9751113","GSM9751114","GSM9751115","GSM9751094","GSM9751095","GSM9751096","GSM9751097","GSM9751098","GSM9751110","GSM9751099","GSM9751111","GSM9751112"],"GPL":["20301"],"GSE":["332586"],"taxon":["Homo sapiens"]}}