Breast cancer is the most commonly diagnosed cancer and second most leading cause of cancer related deaths in women. Importantly, women are much more likely to die from metastatic progression of disease rather than primary tumors. Tumor cells are surrounded and supported by the tumor microenvironment, and current research indicates that stromal cells and extracellular matrix molecules influence and promote metastatic progression. Features of the tumor microenvironment such as alignment of collagen fibers and density influence cell motility, invasion, and subsequent metastasis. It has been shown that increased stromal collagen, increased collagen crosslinking, stiffness of matrices, and increased radial alignment of collagen fibers near tumors is correlated with metastasis and is prognostic for worse outcomes, however the mechanism behind how this change in the stroma occurs is not known. The Longmore lab recently demonstrated that the cell surface molecule DDR2 (Discoidin Domain Receptor 2) positively regulates breast cancer metastasis. When DDR2 depleted tumor cells were implanted into the breast of syngeneic wild-type mice, the associated stroma was less aligned and fewer metastases were observed, indicating a role for DDR2 in stromal remodeling in tumor cells. This experiment did not rule out a role for the matrix producing cancer associated fibroblasts (CAFs), and, importantly, DDR2 ubiquitous null mice have decreased tumor desmoplasia and metastasis in a PyMT genetic model of breast cancer. When DDR2 positive tumor cells were implanted into the breast of DDR2 global null mice, nearly zero metastases were observed, indicating that the activity of DDR2 in the host microenvironment is required for metastasis. Further, preliminary data from conditional deletion of DDR2 in breast tumor stromal cells using FSP1-Cre show a significant decrease in lung metastasis. Finally, in ex vivo preliminary experiments, DDR2 depleted CAFs produce a disorganized ECM, indicating that DDR2 is required in CAFs for matrix alignment. The specific cellular mechanisms and signaling events downstream of DDR2 activation which regulate stromal organization remain unknown and will be studied in the aims of this proposal. The role of DDR2 in tumor cells and CAFs will be parsed out and whether DDR2 affects production of matrix, remodeling of existing matrix, or both will be determined. The downstream signaling pathways of DDR2 that effect the change in stroma alignment will be elucidated, and this project further aims to study the in vivo effect of breast CAF DDR2 on distant metastasis in mice.
These aims will be tested in ex vivo models of matrix production and remodeling and in vivo analyses in mice of tumor pathology, tumor stromal signature, and lung metastasis. These advances will serve to further illustrate how changes in the tumor microenvironment can promote metastasis and identify potential targets for therapeutic intervention.
Breast cancer affects hundreds of thousands of women each year, and the majority of breast cancer related deaths are due to metastatic progression. Tumor-stromal interactions are important in the maintenance of tumor cell invasive potential, and it has been shown that changes in extracellular matrix organization and architecture near tumors is correlated with tumor metastasis. The mechanism by which this process occurs is not known, and further understanding of how alterations in the tumor microenvironment promote metastasis is crucial to the development of better cancer treatments.
|Sewell-Loftin, Mary Kathryn; Bayer, Samantha Van Hove; Crist, Elizabeth et al. (2017) Cancer-associated fibroblasts support vascular growth through mechanical force. Sci Rep 7:12574|