Abstract

Most pancreatic ductal adenocarcinoma (PDAC) develops from pancreatic epithelial cells bearing activating mutant KRAS genes through precancerous lesions, i.e. acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). During pancreatic tumorigenesis, Hes1 expression starts with the transition from acinar cells to ADM, and continues during PanIN and PDAC formation, but the role of Hes1 in pancreatic tumorigenesis is not fully elucidated. Here we show that Hes1 plays an essential role in the initiation and progression of KRAS-driven pancreatic tumorigenesis. In vitro, activation of MAPK signaling due to EGF or mutant KRAS activation induced sustained Hes1 expression in pancreatic acinar cells. In vivo, acinar cell-specific activation of mutant KRAS by Elastase1-CreERT2;KrasG12D induced ADM/PanIN formation with Hes1 expression in mice, and genetic ablation of Hes1 in these mice dramatically suppressed PanIN formation. Gene expression analysis and lineage tracing revealed that Hes1 regulates acinar-to-ductal reprogramming-related genes and, in a Hes1-deficient state, mutant Kras-induced ADM could not progress into PanIN, but re-differentiated into acinar cells. In the Elastase1-CreERT2;KrasG12D;Trp53R172H mouse PDAC model, genetic ablation of Hes1 completely blocked PDAC formation by keeping PanIN lesions in low-grade conditions, in addition to reducing the occurrence of PanIN. Together, these findings indicate that mutant KRAS-induced Hes1 plays an essential role in PDAC initiation and progression by regulating acinar-to-ductal reprogramming-related genes.

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Acknowledgements

We wish to thank Yuta Kawamata for excellent technical support. Concentration of lentivirus particles with an ultracentrifuge was performed at the Medical Research Support Center, Graduate School of Medicine, Kyoto University.

Funding

This work was supported by the JSPS and MEXT KAKENHI Grant Numbers 15J05143, 16K09395, and 17H06803; AMED P-DIRECT Grant Number 15cm0106120h0002.

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Affiliations

  1. Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    • Yoshihiro Nishikawa
    • , Yuzo Kodama
    • , Masahiro Shiokawa
    • , Tomoaki Matsumori
    • , Saiko Marui
    • , Katsutoshi Kuriyama
    • , Takeshi Kuwada
    • , Yuko Sogabe
    • , Nobuyuki Kakiuchi
    • , Teruko Tomono
    • , Atsushi Mima
    • , Toshihiro Morita
    • , Tatsuki Ueda
    • , Motoyuki Tsuda
    • , Yuki Yamauchi
    • , Yojiro Sakuma
    • , Yuji Ota
    • , Takahisa Maruno
    • , Norimitsu Uza
    • , Tsutomu Chiba
    •  & Hiroshi Seno
  2. Department of Gastroenterology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan

    • Yuzo Kodama
  3. Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011, Japan

    • Motonari Uesugi
  4. Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Uji, Kyoto, 611-0011, Japan

    • Motonari Uesugi
    •  & Ryoichiro Kageyama
  5. Institute for Frontier Life and Medical Sciences, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto, 606-8507, Japan

    • Ryoichiro Kageyama
  6. Kansai Electric Power Hospital, 2-1-7 Fukushima, Fukushima-ku, Osaka, 553-0003, Japan

    • Tsutomu Chiba

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

All animal care and experiments were conducted following the guidelines for the Japan’s Act on Welfare and Management of Animals. All animal experiments described herein were approved by the Kyoto University Graduate School (Kyoto, Japan).

Informed consent

Written informed consent for the use of resected tissues was obtained from all patients in accordance with the Declaration of Helsinki.

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Correspondence to Yuzo Kodama.

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DOI

https://doi.org/10.1038/s41388-019-0718-5