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神经黏附素-2-YAP 轴调控胰腺上皮内瘤变的进展。

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

机构信息

Department of Oncology, University of Torino, 10043, Orbassano, Italy.

Candiolo Cancer Institute-IRCCS-FPO, 10060, Candiolo, Italy.

出版信息

EMBO Rep. 2024 Apr;25(4):1886-1908. doi: 10.1038/s44319-024-00104-x. Epub 2024 Feb 27.

DOI:10.1038/s44319-024-00104-x
PMID:38413734
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11014856/
Abstract

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.

摘要

胰腺导管腺癌（PDAC）是一种预后极差的肿瘤，起源于称为胰腺上皮内瘤变（PanIN）的前体病变。从低级别到高级别 PanIN 的进展被认为是肿瘤的起始，需要更深入地了解这种转变。在这里，我们表明突触分子神经粘连蛋白-2（NLGN2）由胰腺外分泌细胞表达，并在接触抑制和上皮极性的调节中发挥关键作用，这是从低级别到高级别 PanIN 转变的特征。NLGN2 在腺泡细胞中定位于紧密连接，在低级别 PanIN 中弥散分布，在高级别 PanIN 和高级别 PDAC 的很大一部分中丢失。从机制上讲，NLGN2 对于 PALS1/PATJ 复合物的形成是必需的，该复合物通过降低 YAP 功能进而诱导接触抑制。我们的结果为 NLGN2 在神经系统外的功能提供了新的见解，并可用于模拟 PanIN 的进展。

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