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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Tomko, Lucas A; Hill, Ryan C; Barrett, Alexander et al. (2018) Targeted matrisome analysis identifies thrombospondin-2 and tenascin-C in aligned collagen stroma from invasive breast carcinoma. Sci Rep 8:12941
Sato, Shinya; Weaver, Alissa M (2018) Extracellular vesicles: important collaborators in cancer progression. Essays Biochem 62:149-163
Sung, Bong Hwan; Weaver, Alissa M (2018) Directed migration: Cells navigate by extracellular vesicles. J Cell Biol 217:2613-2614
Maas, Sybren L N; Breakefield, Xandra O; Weaver, Alissa M (2017) Extracellular Vesicles: Unique Intercellular Delivery Vehicles. Trends Cell Biol 27:172-188
Sung, Bong Hwan; Weaver, Alissa M (2017) Exosome secretion promotes chemotaxis of cancer cells. Cell Adh Migr 11:187-195
Ishihara, Seiichiro; Inman, David R; Li, Wan-Ju et al. (2017) Mechano-Signal Transduction in Mesenchymal Stem Cells Induces Prosaposin Secretion to Drive the Proliferation of Breast Cancer Cells. Cancer Res 77:6179-6189
Erdogan, Begum; Ao, Mingfang; White, Lauren M et al. (2017) Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin. J Cell Biol 216:3799-3816