title: Loss of desmoglein 2 promotes tumorigenic behavior in pancreatic cancer cells.
abstract: The ability to maintain cell-cell adhesion is crucial for tissue integrity and organization. Accordingly, loss of cohesiveness plays a critical role in cancer invasion and metastasis. Desmosomes are cell junctions providing strong intercellular adhesive strength and dysregulation of desmosomal constituents contributes to cancer progression through altered cell signaling pathways. Here, we focused on the desmosomal adhesion molecules Desmoglein 2 (Dsg2) and Desmocollin 2 (Dsc2), and their contribution to migration and invasion in pancreatic cancer cells. Silencing of Dsg2 but not Dsc2 resulted in loss of cell cohesion and enhanced migration, and invasion of pancreatic adenocarcinoma cells. To identify potential pathways regulated by Dsg2, we performed kinase arrays and detected the activity of ERK and growth factor receptors to be significantly enhanced in Dsg2-deficient cells. Consequently, inhibition of ERK phosphorylation in Dsg2 knockdown cells normalized migration. Loss of Dsg2 resulted in reduced levels of the desmosomal adapter protein and transcriptional regulator Plakoglobin (PG) in an ERK-dependent manner, whereas other desmosomal molecules were not altered. Overexpression of PG rescued enhanced migration induced by silencing of Dsg2. These results identify a novel pro-migratory pathway of pancreatic cancer cells in which loss of Dsg2 reduces the levels of PG via deregulated MAPK signaling.
authors.affiliation: Department I, Institute of Anatomy and Cell Biology, Ludwig-Maximilians-Universität Munich, Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Hütz
authors.affiliation: Department I, Institute of Anatomy and Cell Biology, Ludwig-Maximilians-Universität Munich, Munich, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Zeiler
authors.affiliation: Department I, Institute of Anatomy and Cell Biology, Ludwig-Maximilians-Universität Munich, Munich, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Sachs
authors.affiliation: Institute of Pathology, Ludwig-Maximilians-Universität Munich, Munich, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Ormanns
authors.affiliation: Department I, Institute of Anatomy and Cell Biology, Ludwig-Maximilians-Universität Munich, Munich, Germany.
authors.forename: Volker
authors.identifier: 0000-0002-1302-5421
authors.initials: V
authors.lastname: Spindler
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D051301:Desmoglein 2 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D051180:Desmoplakins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D020935:MAP Kinase Signaling System; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D010179:Pancreas / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051185:gamma Catenin
chemical_list: D051301:Desmoglein 2; D051180:Desmoplakins; C495292:JUP protein, human; D051185:gamma Catenin
keywords: desmoglein; desmosome; intercellular adhesion; migration; pancreatic cancer