Exosomes Mediate Stromal Mobilization of Autocrine Wnt-PCP Signaling in Breast Cancer Cell Migration

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. º Fibroblast exosomes promote BCC protrusive activity, motility, and invasion º PCP signaling is required for exosome stimulation of BCC motility and invasion º Core PCP pathway components distribute asymmetrically in exosome-stimulated BCCs º BCC-produced Wnt tethers to fibroblast exosomes upon their internalization by BCCs Wnt signals from stromal fibroblasts transmitted in exosomes activate the planar cell polarity pathway in breast cancer cells, promoting invasive behavior, suggesting one mechanism by which the tumor microenvironment can stimulate malignancy in a primary tumor.