Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Drug Discovery Medicine, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan; DSP Cancer Institute, Sumitomo Dainippon Pharma Co., Osaka, Japan.
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Gastroenterology. 2022 Aug;163(2):466-480.e6. doi: 10.1053/j.gastro.2022.04.020. Epub 2022 Apr 25.
BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) arises from several types of premalignant lesions, including intraductal tubulopapillary neoplasm (ITPN); however, the molecular pathogenesis of ITPN remains unknown.
We performed studies with Hnf1b-Cre; Pten; Arid1a mice to investigate the consequence of genetic deletion of Arid1a in adult pancreatic ductal cells in the context of oncogenic PI3K/Akt pathway activation.
Simultaneous deletion of Arid1a and Pten in pancreatic ductal cells resulted in the development of ITPN, which progressed to PDAC, in mice. Simultaneous loss of Arid1a and Pten induced dedifferentiation of pancreatic ductal cells and Yes-associated protein 1/Transcriptional coactivator with PDZ-binding motif (YAP/TAZ) pathway activation. Consistent with the mouse data, TAZ expression was found elevated in human ITPNs and ITPN-derived PDACs but not in human intraductal papillary mucinous neoplasms, indicating that activation of the TAZ pathway is a distinctive feature of ITPN. Furthermore, pharmacological inhibition of the YAP/TAZ pathway suppressed the dedifferentiation of pancreatic ductal cells and development of ITPN in Arid1a and Pten double-knockout mice.
Concurrent loss of Arid1a and Pten in adult pancreatic ductal cells induced ITPN and ITPN-derived PDAC in mice through aberrant activation of the YAP/TAZ pathway, and inhibition of the YAP/TAZ pathway prevented the development of ITPN. These findings provide novel insights into the pathogenesis of ITPN-derived PDAC and highlight the YAP/TAZ pathway as a potential therapeutic target.
胰腺导管腺癌（PDAC）起源于几种癌前病变，包括导管内管状乳头状肿瘤（ITPN）；然而，ITPN 的分子发病机制尚不清楚。
我们使用 Hnf1b-Cre; Pten; Arid1a 小鼠进行研究，以调查在致癌 PI3K/Akt 途径激活的情况下，成年胰腺导管细胞中 Arid1a 的遗传缺失对 ITPN 的影响。
胰腺导管细胞中同时缺失 Arid1a 和 Pten 导致 ITPN 的发生，继而在小鼠中发展为 PDAC。同时缺失 Arid1a 和 Pten 诱导胰腺导管细胞去分化和 Yes 相关蛋白 1/含 PDZ 结合基序的转录共激活因子（YAP/TAZ）途径激活。与小鼠数据一致，在人类 ITPN 和 ITPN 衍生的 PDAC 中发现 TAZ 表达升高，但在人类导管内乳头状黏液性肿瘤中未发现，表明 TAZ 途径的激活是 ITPN 的一个显著特征。此外，YAP/TAZ 途径的药理学抑制抑制了 Arid1a 和 Pten 双敲除小鼠中胰腺导管细胞的去分化和 ITPN 的发展。
成年胰腺导管细胞中同时缺失 Arid1a 和 Pten 通过异常激活 YAP/TAZ 途径诱导小鼠发生 ITPN 和 ITPN 衍生的 PDAC，抑制 YAP/TAZ 途径可预防 ITPN 的发生。这些发现为 ITPN 衍生的 PDAC 的发病机制提供了新的见解，并强调了 YAP/TAZ 途径作为潜在的治疗靶点。
