A neuroligin-2-YAP axis regulates progression of pancreatic intraepithelial neoplasia

Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a dismal prognosis that arises from precursor lesions called pancreatic intraepithelial neoplasias (PanINs). Progression from low- to high-grade PanINs is considered as tumor initiation, and a deeper understanding of this switch is needed. Here, we show that synaptic molecule neuroligin-2 (NLGN2) is expressed by pancreatic exocrine cells and plays a crucial role in the regulation of contact inhibition and epithelial polarity, which characterize the switch from low- to high-grade PanIN. NLGN2 localizes to tight junctions in acinar cells, is diffusely distributed in the cytosol in low-grade PanINs and is lost in high-grade PanINs and in a high percentage of advanced PDACs. Mechanistically, NLGN2 is necessary for the formation of the PALS1/PATJ complex, which in turn induces contact inhibition by reducing YAP function. Our results provide novel insights into NLGN2 functions outside the nervous system and can be used to model PanIN progression. Synopsis NLGN2 regulates contact inhibition and epithelial polarity, which are altered in high-grade PanIN and PDAC, where NLGN2 expression is lost. NLGN2 promotes PALS1/PATJ polarity complex formation, which recruits YAP and reduces its function in vitro. NLGN2 is expressed in tight junctions of exocrine pancreas and low-grade PanINs, but reduced in high-grade PanINs and PDAC. NLGN2 expression is necessary for cyst polarization and maintenance of contact inhibition in vitro. NLGN2 interacts with PATJ, promoting its interaction with PALS1 and inactivation of YAP in confluent cells. NLGN2 regulates contact inhibition and epithelial polarity, which are altered in high-grade PanIN and PDAC, where NLGN2 expression is lost. NLGN2 promotes PALS1/PATJ polarity complex formation, which recruits YAP and reduces its function in vitro.