胰腺导管腺癌（PDAC）的发展是一个经过多步骤深入研究的过程，然而早期诊断和有效治疗仍然不尽如人意。Notch信号通路在PDAC中的作用存在争议，既有促癌作用，也有拮抗作用。因此，有必要对潜在的分子机制有更为深入的了解。本研究重点关注Notch通路中的接收转录因子RBPJ，在PDAC中的表达模式进行了研究，并在胰腺癌发展的小鼠模型和急性胰腺炎再生过程中对其功能进行了表征。我们使用条件性转基因小鼠模型来对成年胰腺中的RBPJ进行功能分析，PDAC前体病变的启动以及胰腺再生。通过RNA测序对胰腺和原代腺功能细胞进行了ADM的检测，并进行了免疫组织化学和全面转录组分析。我们发现，在一部分人类PDAC标本中，RBPJ的表达降低。通过Ptf1α-CreERT驱动的RBPJ耗竭转基因小鼠模型显示出其在成年腺体细胞的稳态和维持中是可有可无的。然而，缺乏RBPJ的原代腺功能细胞在体外经历了腺体向导管的分化。重要的是，RBPJ缺陷背景下的致癌性KRAS表达促进了具有大量纤维化基质形成的PanIN病变的发展。有趣的是，RNA-seq数据显示与细胞因子/趋化因子和细胞外基质变化相关的转录谱。此外，缺乏RBPJ延缓了急性胰腺炎的进程，并在KRASG12D表达背景下严重受损。我们的研究结果表明，PDAC患者中RBPJ的下调解除了Notch靶基因的抑制作用，并促进了KRAS介导的胰腺腺体细胞转化和纤维化发展。版权所有© 2023 The Authors. Elsevier Inc.发表。保留所有权利。

Development of pancreatic ductal adenocarcinoma (PDAC) is a multi-step process intensively studied, however precocious diagnosis and effective therapy still remain unsatisfactory. The role for Notch signaling in PDAC has been discussed controversially as both, cancer-promoting and -antagonizing functions have been described. Thus, an improved understanding of the underlying molecular mechanisms is necessary. Here, we focused on RBPJ, the receiving transcription factor in the Notch pathway, examined its expression pattern in PDAC and characterized its function in mouse models of pancreatic cancer development and in the regeneration process after acute pancreatitis.Conditional transgenic mouse models were used for functional analysis of RBPJ in the adult pancreas, initiation of PDAC precursor lesions, and pancreatic regeneration. Pancreata and primary acinar cells were tested for ADM together with immunohistology and comprehensive transcriptional profiling by RNA-sequencing.We identified reduced RBPJ expression in a subset of human PDAC specimens. Ptf1α-CreERT driven depletion of RBPJ in transgenic mice revealed that its function is dispensable for the homeostasis and maintenance of adult acinar cells. However, primary RBPJ-deficient acinar cells underwent acinar-to-ductal differentiation in ex vivo. Importantly, oncogenic KRAS expression in the context of RBPJ deficiency facilitated the development of PanIN lesions with massive fibrotic stroma formation. Interestingly, RNA-seq data revealed transcriptional profile associated with the cytokine/chemokine and extracellular matrix changes. In addition, lack of RBPJ delays the course of acute pancreatitis and critically impairs it in the context of KRASG12D expression.Our findings imply that downregulation of RBPJ in PDAC patients derepresses Notch targets and promotes KRAS-mediated pancreatic acinar cells transformation and desmoplasia development.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.