https://scholars.lib.ntu.edu.tw/handle/123456789/641422
標題: | Oncogenic KRAS, Mucin 4, and Activin A-Mediated Fibroblast Activation Cooperate for PanIN Initiation | 作者: | Hu, Chun-Mei Huang, Chien-Chang Hsu, Min-Fen Chien, Hung-Jen Wu, Pei-Jung Chen, Yi-Ing YUNG-MING JENG Tang, Shiue-Cheng Chung, Mei-Hsin Shen, Chia-Ning Chang, Ming-Chu Chang, Yu-Ting YU-WEN TIEN Lee, Wen-Hwa |
關鍵字: | Kras; Muc4; PanIN; activin A; αSMA+ fibroblast | 公開日期: | 十二月-2023 | 卷: | 10 | 期: | 36 | 來源出版物: | Advanced science (Weinheim, Baden-Wurttemberg, Germany) | 摘要: | Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN formation remain elusive. Here, optic-clear 3D histology is used to analyze entire pancreases of 2-week-old Pdx1-Cre; LSL-KrasG12D/+ (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with αSMA+ fibroblasts in both transgenic mice and human specimens. Mechanistically, KrasG12D/+ pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN-associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic KrasG12D/+ -driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/641422 | ISSN: | 2198-3844 2198-3844 |
DOI: | 10.1002/advs.202301240 |
顯示於: | 醫學系 |
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