Paula J. McKeown-Longo, PhD

Chronic inflammation and tissue fibrosis are believed to be major contributors to the development and progression of solid tumors. Tumor progression is accompanied by extensive biochemical and mechanical remodeling of the fibronectin matrix within the tumor stroma. This remodeling includes the upregulation of the EDA isoform of fibronectin, proteolytic release of fibronectin fragments and mechanically induced changes in fibronectin secondary structure. The contribution of this remodeling to the initiation and maintenance of tissue inflammation and fibrosis is not well understood. Structurally, fibronectin is organized into independently folded domains, termed Type I, II and III. These domains can function as ligands for cell surface receptors and as binding sites for other matrix molecules, cytokines and growth factors.  Our laboratory is studying the role of specific fibronectin Type III domains in the expression of inflammatory cytokines and matrix remodeling genes by stromal fibroblasts. We have identified the Type III-1 and alternatively spliced EDA domains of fibronectin as ligands for Toll-like Receptors (TLRs) on fibroblast cells. Current projects are focused on the identification and characterization of the TLR complexes and downstream signaling pathways which regulate expression of inflammatory and fibrotic proteins in response to fibronectin.