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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE256506 | GEO | 2026/09/08

REPOSITORIES: GEO

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Project description:Ewing sarcoma is a highly aggressive tumor characterized by a translocation between members of the FET family of RNA binding proteins and one of several ETS transcription factors, with the most common translocation being EWS-FLI1. EWS-FLI1 leads to changes in gene expression through mechanisms that are not completely understood. We performed RNA sequencing analysis on primary pediatric human mesenchymal progenitor cells (pMPCs) expressing EWS-FLI1 in order to identify novel target genes. This analysis identified lnc277 as a previously uncharacterized long non-coding RNA upregulated by EWS-FLI1 in pMPCs. Inhibiting the expression of lnc277 diminished the ability of Ewing sarcoma cell lines to proliferate and form colonies in soft agar whereas inhibiting lnc277 had no effect on other cell types tested. By analyzing gene expression after shRNA knockdown, we found that both EWS-FLI1 and lnc277 repressed many more genes that they induced and that a significant fraction of EWS-FLI1 repressed targets were also repressed by lnc277. Analysis of primary human Ewing sarcoma RNA sequencing data further supports a role for lnc277 in mediating gene repression. We identified hnRNPK as an RNA binding protein that interacts directly with lnc277. We found a significant overlap in the genes repressed by hnRNPK and those repressed by both EWS-FLI1 and lnc277, suggesting that hnRNPK participates in lnc277 mediated gene repression. Thus, lnc277 is a previously uncharacterized long non-coding RNA downstream of EWS-FLI1 that facilitates the development of Ewing sarcoma via the repression of target genes. Our studies identify a novel mechanism of oncogenesis downstream of a chromosomal translocation and underscore the importance of lncRNA-mediated gene repression as a mechanism of EWS-FLI1 transcriptional regulation. RNA from primary human bone marrow derived mesenchymal cells either control or with inducible expression of EWS-FLI1 for 13 days was used to prepare PolyA selected cDNA libraries.

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

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