Krawczynska Natalia, Wang Yu, Lim Ki, Das Gupta Anasuya, Lenczowski Adam, Abughazaleh Marwan, Bendre Shruti V, Kockaya Lara I, Schane Claire P, Fei Yifan, Hernandez Alvaro G, Drnevich Jenny, Chan Jefferson, Dobrucki Lawrence W, Boppart Marni D, Ostrander Julie, Nelson Erik R
Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana Illinois, 61801 USA.
Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana Illinois, 61801 USA.
bioRxiv. 2024 Aug 2:2024.08.02.606061. doi: 10.1101/2024.08.02.606061.
Small extracellular vesicles (sEVs) are emerging as critical mediators of intercellular communication in the tumor microenvironment (TME). Here, we investigate the mechanisms by which sEVs derived from neutrophils treated with the cholesterol metabolite, 27-hydroxycholesterol (27HC), influence breast cancer progression. sEVs released from 27HC treated neutrophils enhance epithelial-mesenchymal transition (EMT) and stem-like properties in breast cancer cells, resulting in loss of adherence, increased migratory capacity and resistance to cytotoxic chemotherapy. Decreased microRNAs (miRs) within the sEVs resulted in activation of the WNT/β-catenin signaling pathway in recipient cells and suggest that this may be a predominant pathway for stem-like phenotype and EMT. Our findings underscore a novel mechanism by which 27HC-modulated neutrophils contribute to breast cancer pathophysiology through EV-mediated intercellular communication, suggesting potential therapeutic targets in cancer treatment.
小细胞外囊泡（sEVs）正成为肿瘤微环境（TME）中细胞间通讯的关键介质。在此，我们研究了用胆固醇代谢物27-羟基胆固醇（27HC）处理的中性粒细胞来源的sEVs影响乳腺癌进展的机制。27HC处理的中性粒细胞释放的sEVs增强了乳腺癌细胞的上皮-间质转化（EMT）和干细胞样特性，导致细胞黏附丧失、迁移能力增加以及对细胞毒性化疗产生抗性。sEVs内微小RNA（miRs）的减少导致受体细胞中WNT/β-连环蛋白信号通路的激活，并表明这可能是干细胞样表型和EMT的主要途径。我们的研究结果强调了一种新机制，即27HC调节的中性粒细胞通过细胞外囊泡介导的细胞间通讯促进乳腺癌病理生理过程，这为癌症治疗提供了潜在的治疗靶点。
