Title: Endothelial-to-Mesenchymal transition in cancer progression and tissue fibrosis
Description: Recent evidence has suggested that endothelial-to-mesenchymal transition (EndMT) may have a significant role in a number of diseases. Although EndMT has been previously studied in heart development, our work has demonstrated that EndMT can also occur postnatally in various pathologic settings, including cancer and fibrosis. During EndMT, resident endothelial cells delaminate from an organized cell layer, negotiate their way out of basement membrane casing, and acquire a mesenchymal phenotype characterized by loss of cell-cell junctions, loss of endothelial markers, gain of mesenchymal markers, and acquisition of invasive and migratory properties. EndMT-derived cells are believed to function as fibroblasts in damaged tissue and may therefore have an important role in tissue remodeling, fibrosis, and tumor growth. The focus of this dissertation is to determine the specific contribution of EndMT in the pathogenesis of cancer and fibrosis, and to address the underlying signaling mechanisms. We show here that EndMT accounts for about 30-50% of fibroblasts that arise during renal fibrosis, depending on the disease model. Fibroblasts are the principle source of extracellular matrix components and are considered to be the primary mediators of organ fibrosis. In the setting of cancer, we demonstrate that about 30% of the fibroblasts arise via EndMT. These so-called cancer-associated fibroblasts (CAFs) alter the tumor microenvironment by depositing matrix molecules and by releasing paracrine factors that directly affect the behavior of various cell types within the tumor.

Finally, we have studied the signaling mechanisms driving EndMT and found that TGF-β-induced EndMT requires both Smad-dependent and Smad-independent mechanisms. The studies presented here have further established EndMT as an important mechanism for fibroblast recruitment. Although previously very little was known about the origin of fibroblasts in damaged tissues, it is now clear that EndMT provides a considerable proportion of these cells. Furthermore, EndMT is likely to be involved in many other disease settings and future studies should address this possibility. Perhaps most importantly, the recent discoveries of EndMT in different diseases suggest that targeting EndMT may be a novel therapeutic strategy that is broadly applicable in a number of clinical settings.