Nuclear GSK-3β and Oncogenic KRas Promote Aqp5+ Pancreatic Duct Stem Cell Expansion. Nuclear GSK-3β and Oncogenic KRas Promote Aqp5+ Pancreatic Duct Stem Cell Expansion

Intraductal papillary mucinous neoplasm (IPMN) represents the most commonly diagnosed precursor lesion of pancreatic ductal adenocarcinoma (PDA), however the cell-of-origin remains unclear. Herein, we show that pancreas-specific activation in mice of nuclear-targeted glycogen synthase kinase-3β and oncogenic KRasG12D leads to the loss of acinar cells, the expansion of ductal cells, and the rapid development of IPMN with low-grade dysplasia. RNA-sequencing identified the expression of several ductal stem cell lineage genes including the water channel AQP5. The Aqp5+ pancreatic ductal cell pool was proliferative, phenotypically distinct from mature pancreatic ductal cells, and deletion of AQP5 limited IPMN development. Significantly, Aqp5 is highly expressed in human IPMN along with GSK-3b suggesting that human preneoplastic lesions likely arise from the expansion of an Aqp5+ pancreatic ductal stem cell. Altogether, these data identify Aqp5+ ductal cells in the mouse and human pancreas as the likely cell-of-origin for IPMN. Overall design: Pancreas from three 4-week old mice were dissociated into single-cell suspension and equal amount of cells from three were then mixed into one sample.

导管内乳头状黏液性肿瘤（Intraductal papillary mucinous neoplasm, IPMN）是目前最常被诊断的胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDA）癌前病变，但其细胞起源仍不明确。本研究证实，在小鼠胰腺中特异性激活核靶向糖原合成酶激酶3β与致癌性KRasG12D，可导致腺泡细胞丢失、导管细胞扩增，并快速形成伴低度异型增生的IPMN。通过RNA测序鉴定出多个导管干细胞谱系相关基因的表达，其中包括水通道蛋白AQP5。表达AQP5的胰腺导管细胞群体具有增殖活性，其表型与成熟胰腺导管细胞存在显著差异；而敲除AQP5可限制IPMN的发生发展。值得注意的是，AQP5与GSK-3β在人IPMN组织中均呈高表达，提示人类癌前病变极有可能起源于AQP5阳性胰腺导管干细胞的扩增。综上，本研究明确小鼠与人类胰腺中的AQP5阳性导管细胞即为IPMN的潜在细胞起源。实验设计：将3只4周龄小鼠的胰腺组织解离为单细胞悬液，取等量细胞混合后构建单个样本。