Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
CAAD-Center for Translational Research on Autoimmune and Allergic Disease, University of Eastern Piedmont, Novara, Italy.
Cancer Res. 2021 Sep 15;81(18):4794-4807. doi: 10.1158/0008-5472.CAN-20-3150. Epub 2021 Jun 30.
HSP90 is secreted by cancer cells into the extracellular milieu, where it exerts protumoral activities by activating extracellular substrate proteins and triggering autocrine signals through cancer cell surface receptors. Emerging evidence indicates that HSP90 co-chaperones are also secreted and may direct HSP90 extracellular activities. In this study, we found that the HSP90 co-chaperone Morgana is released by cancer cells and, in association with HSP90, induces cancer cell migration through TLR2, TLR4, and LRP1. In syngeneic cancer mouse models, a mAb targeting Morgana extracellular activity reduced primary tumor growth via macrophage-dependent recruitment of CD8 T lymphocytes, blocked cancer cell migration, and inhibited metastatic spreading. Overall, these data define Morgana as a new player in the HSP90 extracellular interactome and suggest that Morgana may regulate HSP90 activity to promote cancer cell migration and suppress antitumor immunity. SIGNIFICANCE: This work suggests the potential therapeutic value of targeting the extracellular HSP90 co-chaperone Morgana to inhibit metastasis formation and enhance the CD8 T-cell-mediated antitumor immune response.
HSP90 由癌细胞分泌到细胞外环境中，通过激活细胞外基质蛋白和通过癌细胞表面受体触发自分泌信号，发挥促肿瘤作用。新出现的证据表明，HSP90 共伴侣也被分泌出来，并可能指导 HSP90 的细胞外活性。在这项研究中，我们发现 HSP90 共伴侣 Morgana 被癌细胞释放，并与 HSP90 一起通过 TLR2、TLR4 和 LRP1 诱导癌细胞迁移。在同基因癌症小鼠模型中，一种针对 Morgana 细胞外活性的 mAb 通过巨噬细胞依赖性募集 CD8 T 淋巴细胞减少了原发性肿瘤生长，阻断了癌细胞迁移，并抑制了转移性扩散。总的来说，这些数据将 Morgana 定义为 HSP90 细胞外相互作用组的一个新成员，并表明 Morgana 可能通过调节 HSP90 活性来促进癌细胞迁移并抑制抗肿瘤免疫。意义：这项工作表明，靶向 HSP90 细胞外共伴侣 Morgana 抑制转移形成和增强 CD8 T 细胞介导的抗肿瘤免疫反应具有潜在的治疗价值。
