Loss of Pancreatic E-Cadherin Causes Pancreatitis-Like Changes and Contributes to Carcinogenesis

Abstract

We created a mouse model in which E-cadherin in the pancreas was specifically deleted. Loss of E-cadherin resulted in pancreatitis-like changes under physiological conditions and contributed to carcinogenesis in the presence of an oncogene.

An Organotypic Microcosm for the Pancreatic Tumor Microenvironment

“…These data suggest that combined Cdh1 deficiency and Kras mutation promote progression to dysplasia and initiate tumor formation. Furthermore, organoid data paralleled in vivo studies revealing transformation to PanIN in nude mice after the induction of Cdh1 loss and Kras alteration [22]. Additionally, organoids harboring Cdh1 loss and Kras mutation were transplanted back into nude mice, which induced the growth of tumors that represented poorly differentiated adenocarcinoma in contrast to mice transplanted with organoids containing either mutation alone.…”

“…Cdh1-deficient organoids were collapsed, as expected from loss of cell adhesion, and showed signs of apoptosis, which morphologically appeared similar to pancreatitis. However, when Kras, one of the most commonly mutated genes in PDAC [15], was altered in organoids, Cdh1-induced apoptosis was reversed and organoids developed dysplastic, tall columnar cells [22]. These data suggest that combined Cdh1 deficiency and Kras mutation promote progression to dysplasia and initiate tumor formation.…”

“…Another important milestone in the progression from normal pancreatic tissue to pancreatitis is the loss of the protein, E-cadherin. The gene Cdh1 encodes E-cadherin, which plays a role in cell-to-cell adhesion [22]. The role of this gene was studied extensively in murine-derived organoids by Kaneta and colleagues [22].…”

“…The gene Cdh1 encodes E-cadherin, which plays a role in cell-to-cell adhesion [22]. The role of this gene was studied extensively in murine-derived organoids by Kaneta and colleagues [22]. Cdh1-deficient organoids were collapsed, as expected from loss of cell adhesion, and showed signs of apoptosis, which morphologically appeared similar to pancreatitis.…”

E-Cadherin: An Enigma in Pancreatic Diseases

“…Besides its role in mediating contact inhibition of proliferation, the cytoplasmic tail of E-cadherin forms a dynamic complex with catenins and regulates several intracellular signal transduction pathways, including Wingless-related integration/β-catenin, phosphoinositide 3-kinase/Protein Kinase B, Rho guanosine triphosphatase, and nuclear factor-κB signaling 2 . In the current issue of Cellular and Molecular Gastroenterology and Hepatology , Kaneta et al 3 have uncovered a previously understudied role of E-cadherin in maintaining tissue homeostasis and tumorigenesis in the pancreas.…”