State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
State Key Laboratory of Southwestern Chinese Medicine Resources, ChengduUniversity of Traditional Chinese Medicine, Chengdu, Sichuan, China.
J Extracell Vesicles. 2024 Jul;13(7):e12493. doi: 10.1002/jev2.12493.
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and chemotherapy is the cornerstone treatment for TNBC. Regrettably, emerging findings suggest that chemotherapy facilitates pro-metastatic changes in the tumour microenvironment. Extracellular vesicles (EVs) have been highly implicated in cancer drug resistance and metastasis. However, the effects of the EVs released from dying cancer cells on TNBC prognosis and corresponding therapeutic strategies have been poorly investigated. This study demonstrated that paclitaxel chemotherapy elicited CXCL1-enriched EVs from apoptotic TNBC cells (EV-Apo). EV-Apo promoted the chemoresistance and invasion of co-cultured TNBC cells by polarizing M2 macrophages through activating PD-L1 signalling. However, baohuoside I (BHS) remarkably sensitized the co-cultured TNBC cells to paclitaxel chemotherapy via modulating EV-Apo signalling. Mechanistically, BHS remarkably decreased C-X-C motif chemokine ligand 1 (CXCL1) cargo within EV-Apo and therefore attenuated macrophage M2 polarization by suppressing PD-L1 activation. Additionally, BHS decreased EV-Apo release by diminishing the biogenesis of intraluminal vesicles (ILVs) within multivesicular bodies (MVBs) of TNBC cells. Furthermore, BHS bound to the LEU104 residue of flotillin 2 (FLOT2) and interrupted its interaction with RAS oncogene family member 31 (RAB31), leading to the blockage of RAB31-FLOT2 complex-driven ILV biogenesis. Importantly, BHS remarkably chemosensitised paclitaxel to inhibit TNBC metastasis in vivo by suppressing EV-Apo-induced PD-L1 activation and M2 polarization of tumour-associated macrophages (TAMs). This pioneering study sheds light on EV-Apo as a novel therapeutic target to chemosensitise TNBC, and presents BHS as a promising chemotherapy adjuvant to improve TNBC chemosensitivity and prognosis by disturbing EV-Apo biogenesis.
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，化疗是 TNBC 的基石治疗方法。遗憾的是，新出现的研究结果表明，化疗促进了肿瘤微环境中的促转移变化。细胞外囊泡（EVs）在癌症耐药性和转移中起着重要作用。然而，来自死亡癌细胞的 EVs 对 TNBC 预后的影响以及相应的治疗策略尚未得到充分研究。本研究表明，紫杉醇化疗从凋亡的 TNBC 细胞中诱导出富含 CXCL1 的 EVs（EV-Apo）。EV-Apo 通过激活 PD-L1 信号促进共培养的 TNBC 细胞的化疗耐药性和侵袭性，通过极化 M2 巨噬细胞。然而，宝藿苷 I（BHS）通过调节 EV-Apo 信号显著增强了共培养的 TNBC 细胞对紫杉醇化疗的敏感性。在机制上，BHS 通过降低 EV-Apo 中的 C-X-C 基序趋化因子配体 1（CXCL1）货物，显著抑制 PD-L1 激活，从而减弱巨噬细胞 M2 极化。此外，BHS 通过减少 TNBC 细胞多泡体（MVBs）腔内小泡（ILVs）的生物发生来减少 EV-Apo 的释放。此外，BHS 结合到绒毛蛋白 2（FLOT2）的 LEU104 残基上并中断其与 RAS 癌基因家族成员 31（RAB31）的相互作用，导致阻断 RAB31-FLOT2 复合物驱动的 ILV 生物发生。重要的是，BHS 通过抑制 EV-Apo 诱导的肿瘤相关巨噬细胞（TAMs）中的 PD-L1 激活和 M2 极化，显著增强紫杉醇对 TNBC 转移的化疗敏感性。这项开创性的研究揭示了 EV-Apo 作为一种新的治疗靶点，通过干扰 EV-Apo 的生物发生来增强 TNBC 的化疗敏感性，并提出 BHS 作为一种有前途的化疗辅助剂，通过改善 TNBC 的化疗敏感性和预后。
