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.

Desmogleins are cell adhesion molecules located both in desmosomes and extradesmosomal regions in the membrane with well‐established roles for intercellular adhesion and signaling. We have previously shown that loss of the most widespread desmoglein, Dsg2, increases malignant behavior and induces a non‐epithelial phenotype through dysregulation of Erk signaling in pancreatic cancer cell lines. Here, we further explored the interdependence of Dsg2 and EGFR/Erk signaling by using Dsg2 knockouts of the pancreatic cancer cell line AsPC‐1. Dsg2 knockout clones showed reduced cell adhesion, enhanced migration and augmented invasion in extracellular matrix. Dsg2 interacted with EGFR as demonstrated in immunoprecipitation experiments. However, upon serum depletion, the increased migratory capacity of Dsg2 knockouts was abrogated and not restored upon EGF treatment. This indicates that increased migration in response to Dsg2 loss is agonist‐dependent but independent of EGF. Furthermore, inhibition of EGFR tyrosin kinase activity using erlotinib was significantly less effective in reducing migration of knockouts compared to wildtype controls. In line with this, erlotinib treatment reduced ERK activity in wildtype controls but not in Dsg2 knockout cells and only partially reverted the non‐epithelial phenotype in response to Dsg2 loss. These data indicate that Dsg2 modulates the activity of EGFR signaling in an agonist‐dependent manner.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.