Abstract P4-12-11: Large Oncosomes Loaded with circPEX13 Enhance Osteoclast Differentiation and Facilitate Breast Cancer Bone Metastasis

Abstract Breast cancer (BC) demonstrates a pronounced tendency to metastasize to bone, leading to severe skeletal complications and mortality. Currently, early precise diagnosis and individual treatment for BC patients with bone metastasis are lacking in clinical practice. A critical stage in the metastatic process involves the establishment of pre-metastatic niches (PMNs) conducive to tumor cell colonization before clinical metastasis occurs. Tumor-derived extracellular vesicles (EVs) play a pivotal role as key mediators in selectively modulating the microenvironment of distant organs to generate PMNs that promote organ metastasis. Our research found that BC with bone tropism significantly downregulated BRMS1L, leading to a reduction of its inhibitory effect on EIF4A3, a pre-mRNA splicing factor that promotes pre-mRNAs circularization by directly binding to their flanking regions. We next identified a novel circular RNA, circPEX13, highly enriched in large oncosomes (LOs), atypical large cancer-derived EVs. These LOs significantly supported bone-directed BC cell metastasis by promoting osteolytic PMN formation, which was crucial for facilitating BC cell growth in bone metastasis. Mechanistically, circPEX13 translocated to the nucleus and bound to the promoter region of NFATc1. Concurrently, circPEX13 acted as a sponge for HDAC1, thereby relieving HDAC1-mediated transcriptional repression of NFATc1. Based on these findings, we discovered that treatment with Zotatifin reduced circPEX13 expression and effectively suppressed BC bone metastasis in BC patient-derived xenograft models. In conclusion, these findings unveil a plausible mechanism whereby LOs secreted by bone metastatic BC cells mediate bone tropism by establishing PMNs in bone, and suggest a potential strategy for treating BC patients with bone metastasis. Citation Format: Jinpeng Luo, Qun Lin, Yu Shi, Zhuxi Duan, Jieer Luo, Ruiyu Hu, Xiaolin Fang, Chang Gong. Large Oncosomes Loaded with circPEX13 Enhance Osteoclast Differentiation and Facilitate Breast Cancer Bone Metastasis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-12-11.