Presentation Title: Mesenchymal Breast Cancer Cells Modulate Extracellular Fibronectin Levels to Enhance Metastatic Outgrowth
Author Name(s): Sarah Libring, Luis Solorio
Author Department and School Affiliation: Weldon School of Biomedical Engineering, Purdue University
Abstract: Breast cancer (BC) is the second leading cause of cancer deaths in women. Analysis of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset strongly links high levels of fibronectin (FN) expression to decreased patient survival. We found that autocrine FN stabilized a mesenchymal phenotype in BC cells. Tumors formed with a heterogenic mix of epithelial-like and mesenchymal-like BC cells increased the rate of metastatic outgrowth by the proliferative epithelial fraction when compared to homogeneous primary tumors. These mesenchymal BC cells secreted robust levels of soluble FN into the microenvironment. However, we establish that none of 15 tested BC cell lines were able to independently organize a FN matrix. Instead, BC cells manipulated the FN matrix production of fibroblasts in a phenotypic and signaling dependent manner. When full BC conditioned media was given to fibroblasts in a paracrine model, epithelial-mesenchymal heterogeneity or plasticity resulted in the largest FN matrix production. In contrast, isolated extracellular vesicles from the homogeneous mesenchymal cells resulted in the most FN. These results support the idea that the mesenchymal BC fraction is necessary for the outgrowth of metastatic disease, in part, through their ability to modulate the FN concentration at primary and secondary sites.