Exosome secretion in breast cancer progression

Exosomes are small extracellular vesicles (EVs) that drive cancer metastasis through paracrine and autocrine signaling. While the role of specific exosome cargoes in this process is not well understood, integrin adhesion receptors have been shown to be involved in the choice of metastatic site. How this occurs is not entirely clear, but could involve binding of exosome- carried integrins to cognate extracellular matrix (ECM) ligands in distant tissues. Another non- exclusive possibility is that exosomal integrins and other adhesion receptors directly initiate assembly of ECM to allow cancer cell survival and invasion at primary tumor sites and colonization of distant metastatic sites. We will investigate these possible functions of exosomes in breast cancer metastasis. In the prior grant cycle, we identified fundamental mechanisms by which both cancer- and stromal-derived exosomes control tumor aggressiveness, including: 1) autocrine promotion of cancer cell migration; 2) fibroblast exosomes are necessary and sufficient to induce assembly of fibronectin and other stromal matrix proteins, both in vitro and in vivo; 3) and fibroblast- secreted exosomes promote both growth and metastasis of primary breast tumors. In addition, we find that adhesion receptors are enriched on small EVs from both cancer cells and fibroblasts. Based on these other findings, we propose the central hypothesis that adhesion molecules carried by breast cancer and fibroblast exosomes drive multiple steps of the metastatic cascade. To test this hypothesis, we will: 1) Test the hypothesis that clustering of integrins and syndecans within exosomes mediates fibronectin (FN) assembly; 2) Test the hypothesis that breast cancer cell exosomes carry unique adhesion molecules that can induce assembly of epithelial-type ECM; 3) Determine the role of exosomal adhesion receptors in promoting breast cancer metastasis.