Center for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
Cell. 2012 Dec 21;151(7):1542-56. doi: 10.1016/j.cell.2012.11.024.
Stroma in the tumor microenvironment plays a critical role in cancer progression, but how it promotes metastasis is poorly understood. Exosomes are small vesicles secreted by many cell types and enable a potent mode of intercellular communication. Here, we report that fibroblast-secreted exosomes promote breast cancer cell (BCC) protrusive activity and motility via Wnt-planar cell polarity (PCP) signaling. We show that exosome-stimulated BCC protrusions display mutually exclusive localization of the core PCP complexes, Fzd-Dvl and Vangl-Pk. In orthotopic mouse models of breast cancer, coinjection of BCCs with fibroblasts dramatically enhances metastasis that is dependent on PCP signaling in BCCs and the exosome component, Cd81 in fibroblasts. Moreover, we demonstrate that trafficking in BCCs promotes tethering of autocrine Wnt11 to fibroblast-derived exosomes. This work reveals an intercellular communication pathway whereby fibroblast exosomes mobilize autocrine Wnt-PCP signaling to drive BCC invasive behavior.
肿瘤微环境中的基质在癌症进展中起着关键作用，但它如何促进转移尚不清楚。外泌体是许多细胞类型分泌的小囊泡，能够实现有效的细胞间通讯。在这里，我们报告称，成纤维细胞分泌的外泌体通过 Wnt-平面细胞极性 (PCP) 信号促进乳腺癌细胞 (BCC) 的突起活性和迁移。我们表明，受外泌体刺激的 BCC 突起显示出核心 PCP 复合物 Fzd-Dvl 和 Vangl-Pk 的互斥定位。在乳腺癌的原位小鼠模型中，BCC 与成纤维细胞的共注射极大地增强了转移，而转移依赖于 BCC 中的 PCP 信号和成纤维细胞中外泌体成分 Cd81。此外，我们证明 BCC 中的运输促进了自分泌 Wnt11 与成纤维细胞衍生的外泌体的连接。这项工作揭示了一种细胞间通讯途径，其中成纤维细胞外泌体动员自分泌 Wnt-PCP 信号来驱动 BCC 的侵袭行为。
