Adherens junctions organize the pancreatic developmental program and manage the evolution of neoplastic epithelium

The intracellular protein p120 catenin aids in maintenance of cell-cell adhesion by regulating E-cadherin stability in adherens junctions. Recent studies have shown essential roles for the cell-cell adhesion apparatus during development and in several human disease states, which has precipitated a rapidly growing interest in the translational biology of these molecules. The work described herein advances our knowledge on the function of adherens junctions during mammalian development and disease states such as injury and neoplastic progression. Chapter 1 provides an overview of established biology of adherens junctions in mammalian development, physiology, and cancer. In chapter 2, we identify a crucial role for p120 catenin in pancreatic development to include regulation of tubulogenesis, branching morphogenesis, acinar cell differentiation, migration of endocrine clusters, and actin cytoskeletal organization. Chapter 2 also reports a critical function for p120 catenin in regulation of inflammation in neonatal and adult mouse pancreas. Chapter 3 explores the biology of p120 catenin in pancreatic disease states to include early pancreatic neoplasia and experimental pancreatitis. Based on literature and in vivo evidence linking p120 catenin to both tumor suppressor and metastasis promoting activities in various tissue contexts, a conditional mouse model approach was used to examine the function of p120 catenin in premalignant pancreatic cancer. Surprisingly, a remarkable epithelial cell delamination (also known as basal epithelial cell extrusion) phenotype was unmasked in the context of acinar-cell specific deletion of p120 catenin and activation of oncogenic Kras in adult mice. This was accompanied by a strong desmoplastic response and significant immune cell infiltration. This mouse model unveiled a new mechanism for pancreatic neoplastic epithelial cell invasion. We identify S1P/S1pr2 as the key mediator of increased basal epithelial cell extrusion in the context of p120 catenin loss in an in vitro system. Chapter 4 presents a brief summary of how the data described herein advances the field. Together, these results establish a completely novel role for p120 catenin in regulation of basal epithelial cell extrusion and invasion. Thesis advisor: Steven D. Leach, M.D Co-mentor: Jennifer M. Bailey, MA, PhD Thesis readers: Steven D. Leach, M.D and Andrew J. Ewald, Ph