KLF4 Is Essential for Induction of Cellular Identity Change and Acinar-to-Ductal Reprogramming during Early Pancreatic Carcinogenesis

Publication date: 14 March 2016
Source:Cancer Cell, Volume 29, Issue 3
Author(s): Daoyan Wei, Liang Wang, Yongmin Yan, Zhiliang Jia, Mihai Gagea, Zhiwei Li, Xiangsheng Zuo, Xiangyu Kong, Suyun Huang, Keping Xie
Understanding the molecular mechanisms of tumor initiation has significant impact on early cancer detection and intervention. To define the role of KLF4 in pancreatic ductal adenocarcinoma (PDA) initiation, we used molecular biological analyses and mouse models of klf4 gain- and loss-of-function and mutant Kras. KLF4 is upregulated in and required for acinar-to-ductal metaplasia. Klf4 ablation drastically attenuates the formation of pancreatic intraepithelial neoplasia induced by mutant Kras^G12D, whereas upregulation of KLF4 does the opposite. Mutant KRAS and cellular injuries induce KLF4 expression, and ectopic expression of KLF4 in acinar cells reduces acinar lineage- and induces ductal lineage-related marker expression. These results demonstrate that KLF4 induces ductal identity in PanIN initiation and may be a potential target for prevention of PDA initiation.

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Teaser

Wei et al. show that KLF4 is a pancreatic ductal fate determinant and is critical for acinar-to-ductal cell reprogramming. Injury and stress signaling can converge to induce KLF4 expression in acinar cells, potentiating the initiation of premalignant pancreatic intraepithelial neoplasia induced by mutant Kras.


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