BACE2 inhibition impairs oncogenic programs and extracellular vesicle-mediated tumor proliferation in Ewing sarcoma

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.