胰腺导管腺癌 (PDAC) 可由前驱病变发展而来，包括胰腺上皮内瘤变 (PanIN) 和导管内乳头状粘液性肿瘤 (IPMN)。先前的研究表明，Acvr1b 的缺失会加速小鼠胰腺中 Kras 介导的乳头状 IPMN 的发育，然而，主要受这些遗传变化影响的细胞类型仍不清楚。我们通过诱导 IPMN 相关突变 - KRASG12D 表达来研究细胞起源的贡献和 Acvr1b 损失 - 特别是小鼠的腺泡细胞（Ptf1aCreER；KrasLSL-G12D；Acvr1bfl/fl 小鼠）或导管细胞（Sox9CreER；KrasLSL-G12D；Acvr1bfl/fl 小鼠）。然后，我们对其胰腺组织进行了 MRI 成像和彻底的组织病理学分析。当腺泡和导管细胞表达 Kras 突变时，Acvr1b 的缺失会增加 PanIN 和 IPMN 样病变的发展。 MRI、免疫组织化学和组织学显示这些小鼠体内存在大的 IPMN 样病变，表现出平坦的胃上皮特征。此外，两种小鼠模型中的囊肿形成均伴有慢性胰腺炎。当腺泡细胞而非导管细胞表达突变型 Kras 并丢失 Acvr1b 时，实验性急性胰腺炎加速了大粘液囊肿和 PanIN 的发展。这些发现表明，在 Kras 癌基因存在的情况下，Acvr1b 的丢失会促进大大小小的癌前病变的发展来自导管细胞和腺泡细胞。然而，IPMN 样表型并不等同于在发育过程中所有胰腺细胞中发生这些突变时观察到的表型。我们的研究强调了细胞环境在外分泌细胞前体病变的发生和进展中的重要性。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Pancreatic ductal adenocarcinoma (PDAC) can develop from precursor lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). Previous studies indicated that loss of Acvr1b accelerates the Kras-mediated development of papillary IPMN in the mouse pancreas, however, the cell type predominantly affected by these genetic changes remains unclear.We investigated the contribution of cellular origin by inducing IPMN associated mutations- KRASG12D expression and Acvr1b loss - specifically in acinar (Ptf1aCreER;KrasLSL-G12D;Acvr1bfl/fl mice) or ductal (Sox9CreER;KrasLSL-G12D;Acvr1bfl/fl mice) cells in mice. We then performed MRI imaging and a thorough histopathological analysis of their pancreatic tissues.The loss of Acvr1b increased the development of PanIN and IPMN-like lesions when either acinar and ductal cells expressed a Kras mutation. MRI, immunohistochemistry and histology revealed large IPMN-like lesions in these mice that exhibited features of flat, gastric epithelium. In addition, cyst formation in both mouse models was accompanied by chronic pancreatitis. Experimental acute pancreatitis accelerated the development of large mucinous cysts and PanIN when acinar, but not ductal, cells expressed mutant Kras and lost Acvr1b.These findings indicate that loss of Acvr1b in the presence of the Kras oncogene promotes the development of large and small precancerous lesions from both ductal and acinar cells. However, the IPMN-like phenotype was not equivalent to that observed when these mutations were made in all pancreatic cells during development. Our study underscores the significance of the cellular context in the initiation and progression of precursor lesions from exocrine cells.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.