In vivo reprogramming drives Kras-induced cancer development

Hirofumi Shibata, Shingo Komura, Yosuke Yamada, Nao Sankoda, Akito Tanaka, Tomoyo Ukai, Mio Kabata, Satoko Sakurai, Bunya Kuze, Knut Woltjen, Hironori Haga, Yatsuji Ito, Yoshiya Kawaguchi, Takuya Yamamoto and Yasuhiro Yamada ()
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Hirofumi Shibata: Kyoto University
Shingo Komura: Kyoto University
Yosuke Yamada: Kyoto University
Nao Sankoda: Kyoto University
Akito Tanaka: Kyoto University
Tomoyo Ukai: Kyoto University
Mio Kabata: Kyoto University
Satoko Sakurai: Kyoto University
Bunya Kuze: Gifu University Graduate School of Medicine
Knut Woltjen: Kyoto University
Hironori Haga: Kyoto University Hospital
Yatsuji Ito: Gifu University Graduate School of Medicine
Yoshiya Kawaguchi: Kyoto University
Takuya Yamamoto: Kyoto University
Yasuhiro Yamada: Kyoto University

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract The faithful shutdown of the somatic program occurs in the early stage of reprogramming. Here, we examined the effect of in vivo reprogramming on Kras-induced cancer development. We show that the transient expression of reprogramming factors (1–3 days) in pancreatic acinar cells results in the transient repression of acinar cell enhancers, which are similarly observed in pancreatitis. We next demonstrate that Kras and p53 mutations are insufficient to induce ERK signaling in the pancreas. Notably, the transient expression of reprogramming factors in Kras mutant mice is sufficient to induce the robust and persistent activation of ERK signaling in acinar cells and rapid formation of pancreatic ductal adenocarcinoma. In contrast, the forced expression of acinar cell-related transcription factors inhibits the pancreatitis-induced activation of ERK signaling and development of precancerous lesions in Kras-mutated acinar cells. These results underscore a crucial role of dedifferentiation-associated epigenetic regulations in the initiation of pancreatic cancers.

Date: 2018
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DOI: 10.1038/s41467-018-04449-5

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