Small extracellular vesicles orchestrated pathological communications between breast cancer cells and cardiomyocytes as a novel mechanism exacerbating anthracycline cardiotoxicity by fueling ferroptosis
Dong Han, Tianhu Wang, Xiaoyao Li, Cheng Qin, Yingjie Zhang, Tingwen Zhou, Shan Gao, Weiwei Zhang, Yongjun Wang, Yan Ma, Feng Cao
Abstract
A) is revealed to mediate the upregulation of miR-338-3p in D-BCCs. D-BCCs-enriched miR-338-3p is packaged in sEVs and transferred into hiCMs in a RBMX-dependent manner, miR-338-3p further targets anti-ferroptotic genes CP, SLC7A11, and GPX4 to facilitate their degradation. Therapeutically, dual-functional decoying sEVs encapsulated with miR-338-3p inhibitor mitigate DOXIC in an orthotopic breast cancer mouse model. Clinically, plasma sEVs isolated from patients experiencing DOXIC enhance DOX-induced ferroptosis in hiCM, which is rescued by miR-338-3p inhibitor. Our findings uncovered for the first time that DOX-treated BCCs exacerbated DOXIC through releasing pro-ferroptotic miR-338-3p-enriched sEVs. Therefore, targeting sEVs-mediated tumor/cardiomyocyte pathological communication may offer a novel approach for the management of DOXIC.