{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE256nnn/GSE256506/"]},"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=GSE256506"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"BACE2 inhibition impairs oncogenic programs and extracellular vesicle-mediated tumor proliferation in Ewing sarcoma","description":"Ewing sarcoma (EWS) is an aggressive pediatric malignancy with poor outcomes in relapsed or metastatic disease and limited targeted therapeutic options. To identify disease-relevant vulnerabilities, we employed a propagatable patient-derived xenograft (pPDX) platform in which serial in vivo passaging enriches for highly aggressive tumors with increased tumor-initiating capacity (TIC). These models preserved the molecular hallmarks of EWS and revealed a transcriptional program associated with tumor aggressiveness. Within this context, β-secretase 2 (BACE2) emerged as constitutively overexpressed and was validated at the protein level across a large primary EWS cohort. Proteomic profiling following BACE2 inhibition demonstrated dose-dependent alterations in pathways governing cell cycle progression and vesicle transport. Genetic and pharmacologic targeting of BACE2 impaired EWS cell proliferation and viability in vitro and abolished tumor-initiating activity in vivo. Mechanistically, BACE2 inhibition disrupted the production and function of EWS-derived extracellular vesicles (EVs), reducing their capacity to promote tumor cell proliferation, activate fibroblasts, and impair endothelial barrier integrity. Importantly, direct intratumoral administration of a BACE2 inhibitor robustly suppressed growth of established EWS PDX tumors. Collectively, these findings identify BACE2 as a previously unrecognized therapeutic vulnerability in Ewing sarcoma and establish BACE2 as a regulator of both tumor-intrinsic oncogenic programs and extracellular vesicle-mediated intercellular communication.","dates":{"publication":"2026/09/08"},"accession":"GSE256506","cross_references":{"GSM":["GSM8102019","GSM8102018","GSM8102017","GSM8102016","GSM8102015","GSM8102014","GSM8102013","GSM8102012","GSM8102011","GSM8102033","GSM8102032","GSM8102010","GSM8102031","GSM8102030","GSM8377459","GSM8377456","GSM8377455","GSM8377458","GSM8377457","GSM8377454","GSM8102009","GSM8102008","GSM8102029","GSM8102007","GSM8102006","GSM8102028","GSM8102027","GSM8102026","GSM8102025","GSM8102024","GSM8102023","GSM8102022","GSM8102021","GSM8102020","GSM8377461","GSM8377460"],"GPL":["16791"],"GSE":["256506"],"taxon":["Homo sapiens"]}}