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RESEARCH INTERESTS - Breast cancer, cell interactions with the extracellular matrix, and immune modulation in the collagen-dense tumor microenvironment.
Understanding molecular mechanisms underlying breast cancer risk due to breast density
Patients with mammographically dense breast tissue have a four to six-fold increased risk of developing breast carcinomas. In fact, 1/3 of all breast cancer cases are attributed to breast density, making it one of the greatest risk factors for carcinoma. Increased breast density is associated with a significant increase in the deposition of extracellular matrix (ECM) components, most notably the protein, collagen. We have developed model systems to understand why increased breast density results in an increased risk for developing breast carcinoma. Additionally, our group uses state of the art imaging approaches to characterize the collagen structure surrounding tumors so that we can better understand the physical relationship between cells and the collagen fibers found in breast tissue. We have identified a set of collagen changes that accompany tumor progression, termed Tumor Associated Collagen Signature (TACS). These changes are characterized by the deposition of bundled, straight collagen (TACS-2) that become oriented perpendicular to the tumor-stromal boundary (TACS-3). Importantly, the presence of TACS-3 collagen is an independent predictor of poor outcome.
Molecular signaling events related to cell interactions with the ECM
Appropriate cellular interactions with the extracellular matrix (ECM) help to establish normal cellular architecture and differentiation. During oncogenic transformation, these normal interactions with the ECM are profoundly altered, resulting in cells that lose their polarization and differentiation, lose anchorage dependent growth control, and acquire a migratory, invasive phenotype. Our lab is interested in understanding, at a molecular level, how cellular interactions with the ECM determine differentiation and epithelial polarization, and how these interactions are altered during carcinogenesis to result in invasive, metastatic carcinoma.
Immunosuppressive signaling within the collagen dense tumor microenvironment
Our lab demonstrated that breast carcinoma is among several solid tumors in which it is clear there is a role for the extracellular matrix in tumor progression. Further investigation into mammary tumor progression identified several mediators of immunosuppression that are dramatically increased when tumors arise in a collagen dense microenvironment, including carcinoma associated fibroblasts (CAFs) and expression of programmed death ligand-1 (PD-L1). It is well documented that CAFs can regulate the immune response within the tumor microenvironment by secreting multiple factors that either inhibit or enhance tumor growth. The cytokines found in the collagen dense tumor microenvironment activate CAFs toward an immunosuppressive phenotype, including expression of PD-L1, to subsequently enhance tumor progression. Recently, antibodies against PD-L1 have been shown to modulate the immune response and this therapy has been effective for certain subtypes of breast carcinoma but anti-PD-L1 therapy has not been tested in collagen-dense breast cancers. Thus, we seek to investigate collagen density in the breast tumor microenvironment as a predictive biomarker for successful immune modulation therapy.