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

• Published in: Cancer cell Vol. 29; no. 3; pp. 324 - 338
• Main Authors: Wei, Daoyan, Wang, Liang, Yan, Yongmin, Jia, Zhiliang, Gagea, Mihai, Li, Zhiwei, Zuo, Xiangsheng, Kong, Xiangyu, Huang, Suyun, Xie, Keping
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14-03-2016
• Subjects: Acinar Cells - metabolism; Acinar Cells - pathology; Animals; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinogenesis - pathology; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Genes, ras - genetics; Humans; Kruppel-Like Transcription Factors - metabolism; Mice; Pancreas - metabolism; Pancreas - pathology; Pancreatic Ducts - metabolism; Pancreatic Ducts - pathology; Precancerous Conditions - genetics; Precancerous Conditions - metabolism; Precancerous Conditions - pathology; Up-Regulation - genetics
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2016.02.005

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 KrasG12D, 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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•KLF4 induces ductal but represses acinar identity in pancreatic acinar cells•KLF4 is required for acinar-to-ductal cell reprogramming•Mutant KRas, injury, and stress signaling converge to activate KLF4 expression•KLF4 synergizes with mutant KRas in initiation of PanIN
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.