Exosomes Mediate Stromal Mobilization of Autocrine Wnt-PCP Signaling in Breast Cancer Cell Migration
Exosomes Mediate Stromal Mobilization of Autocrine Wnt-PCP Signaling in Breast Cancer Cell Migration
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DOI：
10.1016/j.cell.2012.11.024
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发表时间：
2012-12-21
期刊：
影响因子：
64.5
通讯作者：
Wrana, Jeffrey L.
中科院分区：
文献类型：
--
作者：
Luga, Valbona;Zhang, Liang;Wrana, Jeffrey L.
肿瘤微环境中的基质在癌症进展中起关键作用，但其如何促进转移尚不清楚。外泌体是由许多细胞类型分泌的小泡，是细胞间通讯的有效模式。在这里，我们报道了成纤维细胞分泌的外泌体通过wnt平面细胞极性（PCP）信号传导促进乳腺癌细胞（BCC）的突出活性和运动。我们发现外泌体刺激的BCC突出显示出核心PCP复合物Fzd-Dvl和Vangl-Pk的互排斥定位。在原位乳腺癌小鼠模型中，bcc与成纤维细胞共注射可显著增强转移，转移依赖于bcc中的PCP信号和成纤维细胞中的外泌体成分Cd81。此外，我们证明贩运bcc可促进自分泌Wnt11粘附到成纤维细胞衍生的外泌体上。这项工作揭示了一种细胞间通讯途径，即成纤维细胞外泌体动员自分泌Wnt-PCP信号来驱动BCC侵袭行为。
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.