Secretion of extracellular exosome vesicles from cells can have profound autocrine and paracrine effects on cellular phenotype. In the tumor microenvironment, exosomes are thought to be important mediators of tumor progression. However, the exact functions of exosomes in tumors are poorly understood. Although not initially thought to be specific exosome cargos, extracellular matrix molecules are frequently identified in association with exosomes and could profoundly affect tumor behavior. The Weaver laboratory recently demonstrated that the matrix molecule fibronectin is specifically targeted to exosomes by interacting with integrin receptors. Furthermore, they have found that secretion of fibronectin-carrying exosomes promotes adhesion formation and cancer cell motility. Finally, their preliminary data indicates that exosome secretion is also important for stromal matrix assembly and alignment, which the Keely lab has demonstrated is an important driver of poor prognosis in breast cancer. Based on these data, the central hypothesis of this project is that both autocrine and paracrine communication via fibroblast and breast cancer exosome secretion drives generation of aligned stromal matrices and aggressive tumor behavior. To test this hypothesis, we will determine the role of exosomes in driving persistent cell migration by breast cancer cells. We will also test the hypothesis that autocrine exosome secretion is critical for stromal matrix assembly and alignment by fibroblasts. Finally, we will define the role of breast cancer- fibroblast exosomal crosstalk in promoting stromal matrix assembly and tumor aggressiveness.
This project is important to human health because it investigates basic mechanisms by which breast cancer and stromal cells interact to promote cancer progression and metastasis. Identification of molecules that drive this process could be used to intervene therapeutically or predict prognosis.
