December
3,
2021
(Drug DELIVERY Specific Seminar)
The Extracellular Matrix and Breast Cancer: Potential Targets for Anti-Cancer Therapies
Breast cancer is one solid tumor for which there is a clear role for the extracellular matrix in disease progression. Work by our group has identified a set of collagen changes that accompany mammary tumor progression, termed Tumor Associated Collagen Signature (TACS). Importantly, the presence of straightened fibers aligned perpendicular to the tumor boundary (TACS-3) is an independent predictor of poor outcome. However, it remains unclear whether reorganization of the collagen matrix is the consequence of mechanical or compositional tissue remodeling. Utilizing matrisome targeted proteomics we investigated the compositional changes in the ECM correlating to collagen fiber reorganization from normal and invasive ductal carcinoma (IDC). We identified a set of 4 ECM proteins, including Fibronectin, Collagen-12a1, tenascin-C and thrombospondin-2, that significantly co-localized with aligned collagen fibers in IDC tissues and are predictive of decreased metastasis-free survival. In additionally, our recent studies determined that interactions between estrogen and the collagen dense tumor microenvironment alter the expression of ECM composition, including several the of the ECM proteins identified in our proteomic analysis, at both the primary and metastatic sites. Interestingly, the changes in the stromal ECM and, specifically, fiber architecture are associated with immunosuppressive signaling and pro-tumor macrophages. Together, these results established importance of fibrotic extracellular matrix in breast cancer progression and the appreciation for biophysical regulation of tumor inflammation and immunosuppressive signaling. Currently, we are developing two separate approaches to target the proteins in the ECM-dense tumor microenvironment for the clinical treatment of breast cancer. These approaches include a novel peptide inhibitor of fibronectin matrix assembly as well as a collagenase-expressing bacterial based delivery vector. Continued development of these therapeutic approaches holds great promise to target breast cancer as well as other ECM-rich solid tumors.
Hosted by Glen Kwon
