A recent paper adds a new facet to the role of the microenvironment in tumorigenesis, showing that stromal-derived exosomes can promote breast cancer cell migration and invasiveness by modulating signaling through the Wnt–planar cell polarity (PCP) pathway (Cell 151, 1542–1556).

Valbona Luga et al. found that fibroblast-conditioned medium promoted the formation of protusions from breast cancer cells as well as their motility, and co-injection of fibroblasts and breast cancer cells into mice led to increased metastasis compared to the injection of cancer cells alone. They then showed that knockdown of core PCP pathway components in cancer cells abrogated the effects of fibroblasts on breast cancer cell motility, suggesting that the fibroblasts mediate motility through the PCP pathway. Similarly, the fibroblast-mediated effects required expression of the Wnt ligand Wnt11 in breast cancer cells. Treatment of the cancer cells with conditioned medium led to the asymmetric distribution of core PCP components and Wnt11 in cell protrusions, analogous to the distribution of such components in planar-polarized epithelial cells.

The authors then identified the active component of the conditioned medium as exosomes expressing the tetraspanin protein CD81. In a gene expression data set from human breast cancers, they showed that CD81 was significantly upregulated in the stroma associated with breast cancer compared with control breast tissue, suggesting that CD81 may also have a role in the tumor-associated stroma in human breast cancer.

Finally, Luga et al. provided mechanistic insights into how stromal exosomes mediate autocrine PCP signaling in breast cancer cells: the exosomes are taken up by the cancer cells by endocytosis, and Wnt11 then associates with the exosomes and is redistributed in the cancer cell, which the authors suggest is important for activating PCP signaling.