Abstract PL1: Stromal Cells and Matrix Remodeling as Essential Regulators of the Tumor Microenvironment

Abstract

Abstract Carcinomas represent complex neo-organs in which extensive communication networks between surrounding non-transformed endothelial, neural, inflammatory and immune cells provide biochemical signals that govern the behavior of malignant epithelial cells. Moreover, the initiation, progression and metastatic spread of malignant cells is in many human carcinomas associated with desmoplasia. Desmoplasia is typically associated with poor prognosis and in many contexts, confers resistance to therapy. Desmoplasia is characterized by activation of mesenchymal-derived stromal cells such as adipocytes and cancer associated fibroblasts (CAFs) and dynamic remodeling of the extracellular matrix that underlies the dramatic physical differences of tumor tissue compared to corresponding normal tissue that result in further alternations in biochemical signals, contribute to a pro-tumorigenic metabolic milieu as well as alterations in biomechanical signals. Recent studies indicate that fibroblasts also play a critical role in regulating inflammatory and immune cell infiltration, intra-tumoral migration and function in primary tumors and metastatic disease. Recent studies have established that the stromal cell component is heterogeneous with subpopulations of CAFs and specific CAF-mediated pathways that either restrain or promote tumor progression. Genetic and immune-based therapy approaches have identified a subset of Fibroblast Activation Protein (FAP)-expressing tumor promoting CAFs in pre-clinical models of multiple types of carcinoma and FAP -expression correlates with worse survival of patients with a variety of carcinomas including breast cancer. Studies demonstrating that FAP+ CAFs promote tumorigenesis through both immune-dependent and immune-independent mechanisms in pre-clinical models will be presented that support efforts to develop FAP+ cell-targeted therapies in combination with cancer cell targeted therapies. In an effort to refine our approach to therapeutically targeting stroma-dependent mechanisms from a cellular to a molecular level, we have also identified the proteolytic activity of FAP, a cell surface serine protease, as a critical molecular pathway by which FAP+ cells exert their pro-tumorogenic effects. We previously demonstrated in models of lung, colon, and pancreatic cancer, that FAP-null mice are protected from tumorigenesis, progression and metastasis. We recently expanded these results to pre-clinical models of breast cancer and investigated whether stroma-dependent mechanisms contribute to the increased risk of breast cancer incidence and/or progression associated with obesity. Using the spontaneous MMTV-neu murine breast cancer model, we found that FAP-null mice showed delayed primary tumorigenesis. In vitro spheroid formation assays revealed a role for FAP+/+ cells in supporting tumorigenesis, while experiments using primary stromal cell-derived matrices (CDMs) also established a role for FAP-mediated matrix remodeling in promoting cancer cell growth. Taken together, these data suggest that stromal cell-expressed FAP has multiple pro-tumorigenic functions in the context of early breast cancer. Citation Format: E Pure. Stromal Cells and Matrix Remodeling as Essential Regulators of the Tumor Microenvironment [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PL1.